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Next Article 
Blood, Vol. 91 No. 4 (February 15), 1998:
pp. 1101-1134
REVIEW ARTICLE
c-kit Ligand and Flt3 Ligand: Stem/Progenitor Cell Factors
With Overlapping Yet Distinct Activities
By
Stewart D. Lyman and
Sten Eirik W. Jacobsen
From the Department of Molecular Genetics, Immunex Corp, Seattle, WA;
and the Stem Cell Laboratory, Department of Internal Medicine,
University Hospital of Lund, Lund, Sweden.
 |
INTRODUCTION |
HEMATOPOIESIS IS A life-long process
responsible for replenishing both hematopoietic progenitor cells and
mature blood cells from a pool of pluripotent, long-term reconstituting
stem cells.1 The daily turnover in a normal adult of
approximately 1012 blood cells is tightly regulated,
involving, in part, a complex interaction between soluble and
membrane-bound stimulatory and inhibitory cytokines and their
corresponding receptors.2-4 The molecular cloning of these
hematopoietic growth factors (HGFs) and their receptors has been
instrumental in delineating the pathways that lead from a single
hematopoietic stem cell to the various terminally differentiated cells
in the hematopoietic system.
Although a number of cytokines have effects on progenitor and stem
cells in vitro or in vivo, two cytokines discovered in the early 1990s,
c-kit ligand and flt3 ligand, appear to have unique and
nonredundant activities on primitive progenitor/stem cells.
Because of the broad range of hematopoietic activities mediated through
interaction of c-kit ligand (KL) and flt3 ligand (FL) with
their receptors, it is beyond the scope of this report to review the
effects of these proteins outside of the hematopoietic system. Rather,
we will focus on the discovery, structure, function, expression, and
biological roles of these two ligand-receptor pairs. Special attention
will be directed towards hematopoietic activities in which KL and FL
show either distinct or synergistic effects. For a more detailed
overview of other hematologic and immunologic effects of KL and FL,
other reviews can be recommended.5-8 Two subjects have been
deliberately left out of this report, because they are deserving of
their own separate reviews (signal transduction pathways involving
c-kit and flt3 and activities of KL and FL outside of the
hematopoietic system).
| |
DISCOVERY OF THE DOMINANT WHITE SPOTTING (W)
LOCUS AND ITS RELATIONSHIP TO THE c-kit TYROSINE KINASE
RECEPTOR |
The W (dominant White spotting) locus in mice was first
described in the early 1900s.9,10 Mice afflicted with
mutations at the W locus were originally identified, as the
name implies, by the presence of a white spot on the bellies of
pigmented mice. Detailed examination of these mice showed that the
mutation was pleiotropic. The mice suffer from defects in germ cell
development (manifested as reproductive difficulties) and in
hematopoiesis (characterized by a macrocytic anemia). Over the years,
at least 20 allelic variants of the W locus have been
described; most have a similar, although not identical,
phenotype.9,10 The W locus is on chromosome 5 and
is one of the most mutable loci in mice.9,10
A central question that remained was what kind of protein the W
locus encoded, and how did it affect so many different tissues. A
breakthrough came in 1988 when it was shown that the W locus encoded a tyrosine kinase receptor known as
c-kit.11,12 The c-kit protein has the same
general structure as four other tyrosine kinase receptors:
c-fms, the receptor for macrophage colony-stimulating factor
(M-CSF)13-15; flt316-19; and both of the
receptors for platelet-derived growth factor (PDGF;
designated as A and B).20-23 Each of these
receptors is approximately 1,000 amino acids in length, has five
Ig-like domains in the extracellular region, and contains a split
catalytic domain in the cytoplasmic region that phosphorylates tyrosine
residues in specific target proteins after activation of the receptor
by ligand. The exact defect in the c-kit receptor has been
identified at the molecular level for a number of alleles of the
W locus24-28 (see section on genetic alterations in
c-kit and KL genes).
| |
THE STEEL (Sl) LOCUS AND ITS RELATIONSHIP TO
W |
Many years after the discovery of the W locus, a mutation in
mice that had a phenotype virtually identical to W mice was
identified.29 Despite the similarities in phenotype, this
new mutation, designated Steel (Sl), was localized to mouse
chromosome 10, so it was clearly not allelic with the W locus
on chromosome 5.10,30 Because mutations on two different
chromosomes had the same complex phenotype that affects pigmentation,
germ cells, and hematopoiesis, researchers hypothesized that there
would be some relationship between the proteins encoded at these two
loci. Elizabeth Russell, who did much of the pioneering research on
both of these mutations, suggested (years before the discovery that the
W locus encoded c-kit and that c-kit was a
receptor) that the W and Sl loci might encode a
receptor and its cognate ligand.10
| |
CLONING OF THE STEEL FACTOR (THE c-kit LIGAND, KL) |
With the recognition that the W locus encoded
c-kit,11,12 the search for the c-kit ligand
began in earnest. A number of approaches were undertaken to identify
the protein encoded at the Sl locus, including chromosome
walking31 and expression cloning. However, the successful
approach turned out to be the purification of the Steel factor protein.
The cloning of a cDNA encoding the Steel factor was reported
simultaneously by three different groups, each of which discovered a
different source of the factor.32-34 All three groups used
a similar approach; they first purified the protein from medium conditioned by a cell line, obtained N-terminal amino acid sequence, and then made degenerate oligonucleotide primers based on the protein
sequence to isolate cDNA clones by polymerase chain reaction (PCR). The
three groups named this protein mast cell growth factor, stem cell
factor, and c-kit ligand (see below). In this review, we will
use the name c-kit ligand (KL) for the protein that binds to
the c-kit receptor and is encoded at the Sl locus on
mouse chromosome 10 (see below).32,35,36
Once the murine and rat KL cDNAs had been cloned, cross-species
hybridization was used to clone KL cDNAs from a number of other
species.33,37-40 The mouse and human proteins are 82%
identical at the amino acid level.
| |
DISCOVERY OF THE Flt3 TYROSINE KINASE RECEPTOR |
In contrast to the discovery of c-kit, analysis of mouse
mutations did not play a role in the discovery of the flt3 receptor. This receptor was isolated independently by two groups using distinct cloning strategies.18,19,41 One group used low stringency hybridization with a DNA probe from the M-CSF receptor (c-fms) to isolate a portion of a related DNA sequence that was named flt3
(fms-like tyrosine kinase 3).41 The partial clone was then used to isolate a full-length receptor clone.18
A second group used degenerate oligonucleotides (based on conserved
regions within the kinase domain of tyrosine kinase receptors) in a
PCR-based strategy to isolate a novel receptor fragment from highly
purified murine fetal liver stem cells.19 This fragment was
used to isolate a full-length receptor clone given the name flk-2
(fetal liver kinase 2). The flt3/flk-2 receptor has also been referred
to as Stk-1 (stem cell kinase-1),17 but this name is not
widely used, perhaps because it has been previously designated to
denote a gene regulating stem cell kinetics42 as well as a
different receptor tyrosine kinase of the met/sea/ron
family.43
Comparison of the murine flt3 and flk-2 receptor sequences showed that
these sequences differ by only two amino acids in their extracellular
domains.44 In contrast, a large number of amino acid
differences were seen in a region near their C-terminal ends. The
murine flt3 receptor sequence has been independently confirmed by
several groups,44-46 and the human receptor sequence is
directly homologous to the murine flt3, but not the murine flk-2
sequence.16,17 No independent confirmation of the sequence
of flk-2 has been reported. Differences between flt3 and flk-2
sequences are not a result of tissue-specific expression of distinct
isoforms.46 The differences in the murine flt3 and flk-2
sequences have never been fully explained, and the validity of the
sequence reported as flk-2 is still unclear.47 As a result
of this, we refer to the receptor as flt3 and to its ligand as flt3
ligand (FL).
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CLONING OF THE LIGAND (FL) FOR THE Flt3 RECEPTOR |
A soluble form of the flt3 receptor was the key reagent used by two
groups to clone FL. Lyman et al48 screened a variety of
cell lines to look for one that expressed a ligand on the cell surface
that was capable of binding the soluble receptor. A murine T-cell line
was identified that specifically bound the soluble flt3 receptor. The
ligand was then cloned from a cDNA expression library made from mRNA
isolated from these cells.
An alternative approach employed by Hannum et al49 used an
affinity column made with the mouse flt3 receptor extracellular domain
to purify FL from medium conditioned by a murine thymic stromal cell
line. N-terminal sequencing of the purified protein generated a short
amino acid sequence, which was then used to design degenerate
oligonucleotide primers to amplify a portion of the FL gene by PCR.
Isolation of this FL gene fragment led to the cloning of a full-length
murine cDNA.
Once the murine FL cDNA had been isolated, it was used to isolate cDNAs
encoding the human gene.49,50 The mouse and human FL
proteins are 72% identical at the amino acid level; homology is
greater in the extracellular region (73%) than in the cytoplasmic domain (57%).
| |
SPECIES SPECIFICITY OF KL AND FL |
No restriction in species specificity has been observed with regard to
FL binding or biological activity. Both the mouse and human ligand
proteins are fully active on cells bearing either the mouse or human
receptors.51 The human FL protein has been found to
stimulate mouse, cat (Janis Abkowitz, University of Washington, Seattle, WA, unpublished data), rabbit,
nonhuman primate, and human cells. This lack of species specificity of
FL is in marked contrast to KL, where the mouse protein is active on
human cells but the human protein has limited activity on murine
cells.33 Analysis of chimeric mouse/human KL proteins has
helped define regions of the protein that regulate its species-specific
action.52
| |
STRUCTURE OF THE c-kit AND Flt3 RECEPTORS |
The murine and human c-kit receptors are each 976 amino acids
in length, have nine potential sites for N-linked glycosylation in
their extracellular domains,53,54 and are glycosylated at one or more of these sites.54,55 Immunoprecipitation shows two proteins of approximately 140 kD and 155 kD54; the
predicted size of the protein backbone alone is approximately 108 kD.
Pulse-chase analysis has shown that the larger 155-kD protein arises
from the smaller protein,56 presumably due to glycosylational processing of the protein from one containing high
mannose carbohydrates to one containing complex carbohydrates. Furthermore, cell surface iodination of c-kit-expressing cells radiolabels only the larger protein.54 The size of the
c-kit protein varies between tissues,55 although
whether this is due to differential glycosylation or expression of
different isoforms is unclear (see below).
The murine (1,000 amino acids) and human (993 amino acids) flt3
receptors have 9 and 10 potential sites for N-linked glycosylation, respectively, in their extracellular domains16-19 and are
also glycosylated at one or more of these sites.44
Immunoprecipitation shows two proteins of 130-143 kD and 155-160 kD44,57,58; the predicted size of the protein backbone
alone is approximately 110 kD. As with c-kit, pulse-chase
analysis has shown that the larger protein arises from the smaller
protein44; again, this most likely results from
glycosylational processing. Consistent with this interpretation is the
finding that only the 158-kD species is found on the cell
surface.44 There do not appear to be any O-linked sugars on
the protein.59
| |
BINDING OF KL AND FL TO THEIR RECEPTORS |
A number of studies have measured the binding affinity of KL to the
c-kit receptor60-64 and that of FL to the flt3
receptor.65 Both high (kd, 16 to 310 pmol/L) and low (kd, 11 to 65 nmol/L) affinity binding of KL to its
receptor have been reported.60,61,63 Some primary cells and
cell lines have only high- affinity sites, whereas others have
both.61,63 Neither the number of receptors per cell nor the
finding of one or two classes of receptors can be correlated with the
ability of cells to proliferate in response to KL.60
The binding affinity of human FL for the flt3 receptor on human myeloid
leukemia cells has been estimated to be 200 to 500 pmol/L,65 and only high-affinity binding is seen. The high
binding affinity of FL for the flt3 receptor is therefore in the same range of affinities as the binding of KL to c-kit.
The c-kit and flt3 receptors each have five Ig-like domains in
their extracellular regions. Mutagenesis studies on c-kit have shown that the first three domains are both necessary and sufficient for binding of ligand66 and that the fourth Ig-like domain
is required for dimerization of the receptor,66 although
this has recently been called into question.67 Several
models have been proposed for binding of KL to
c-kit,66-71 but it is beyond our scope to review
these studies. Whatever the mechanism responsible for the formation of
the complex, the ultimate result is that a dimeric form of the ligand
is associated with a dimeric form of the receptor, which results in
signal transduction. Although similar studies have not been performed
with FL and flt3 receptors, a similar process most likely occurs with
this ligand-receptor pair.
| |
ISOFORMS OF THE c-kit AND Flt3 RECEPTORS |
Analysis of independently derived cDNA clones has shown that there are
two isoforms of both the murine and human c-kit-encoded protein.72 These c-kit receptor isoforms differ by
four amino acids (glycine-asparagine-asparagine-lysine, abbreviated
GNNK) that are either present or absent just upstream of the
transmembrane domain. The different isoforms result from alternative
splicing of c-kit mRNAs at a cryptic splice donor site located
at the 3 end of exon 9.73 Although it is not clear if
physiologic differences occur because of ligand signaling via one
c-kit isoform versus another, ligand-independent constitutive
phosphorylation of the receptor occurs only in the isoform missing
these four amino acids.72
Crosier et al74 examined expression of the two c-kit
isoforms in both leukemic cell lines and in primary acute myeloid
leukemias; both isoforms appeared to be expressed in all of the cells
examined, with the ratio of GNNK to GNNK+
isoforms ranging from 10:1 to 15:1. A second study confirmed the
expression of both isoforms in a series of acute myeloid
leukemias.75
In addition to the isoforms discussed above, other variants have been
seen in the c-kit receptor. Alternative splicing of mRNAs has
been shown to insert an extra serine residue in the cytoplasmic domain
at position 715; a survey of human cell lines and acute myeloid
leukemia samples shows that both of these isoforms are normally
expressed.74
Finally, soluble c-kit receptors are produced by some
hematopoietic cell lines in culture,64 and a soluble
version of c-kit has been found in human serum at high levels
(324 ± 105 ng/mL).76 How this soluble c-kit
receptor is generated is unknown, although it does appear capable of
binding KL.60,64 In each of the cases described above, the
physiologic significance, if any, of the receptor variant is unknown.
Fewer isoforms of the flt3 receptor have been reported than have been
seen with c-kit. One isoform of the murine flt3 receptor is
missing the fifth of the five Ig-like regions in the extracellular domain as a result of the skipping of two exons during
transcription.77 This alternative isoform is present at
lower levels than the wild-type receptor, although it is able to bind
ligand and is phosphorylated as a result of this binding. Thus, the
fifth Ig domain of flt3 is not required for either ligand binding or
receptor phosphorylation. Similarly, the c-kit receptor
requires only the first three Ig-like domains for ligand
binding.66 The physiologic significance of this flt3
receptor isoform is presently unknown, and a soluble version has not
yet been identified in human serum.
| |
STRUCTURES OF THE KL AND FL PROTEINS |
The KL and FL proteins are structurally similar to each other (as
described below)48-50 and to M-CSF.78 The
primary translation product of the KL gene is a type 1 transmembrane
protein, ie, the N-terminus of the protein is located outside of the
cell. This protein is biologically active on the cell
surface.79 The murine and human KL proteins are each 273 amino acids in length, with a 25 amino acid leader, a 185 amino acid
extracellular domain, a 27 amino acid transmembrane domain, and a 36 amino acid cytoplasmic tail.
The murine32,79 KL protein has four potential sites for
N-linked sugar addition; the human protein has five. KL made by Buffalo
rat liver cells is N-glycosylated in a heterogeneous fashion and
probably contains O-linked sugars. Analysis of human KL produced by
Chinese hamster ovary (CHO) cells shows that it is glycosylated in a
somewhat different manner than the rat protein and that it also
contains O-linked sugars.80
Circular dichroism spectra of KL shows that it has considerable
secondary structure, including both  helical and  sheets.80 There are four cysteine residues that are
conserved between KL, FL, and M-CSF. In the case of KL, these form
two intramolecular disulfide bonds that establish the
three-dimensional structure of the protein.81 Although KL
forms homodimers in solution, they are not covalently
linked.80 KL is thus different from M-CSF, which contains
three intramolecular disulfide bonds and an unpaired cysteine residue
that forms an intermolecular disulfide bond.82 Preliminary
data suggest that FL also contains three intramolecular disulfide bonds
and exists as a noncovalently linked homodimer (Rick Remmele, Immunex,
Seattle, WA; unpublished observation).
Mutagenesis studies of mouse and human KL have identified a core region
that is required for biological activity; this region constitutes the
major portion of the extracellular domain and encompasses all four of
the cysteine residues conserved between KL, FL, and
M-CSF.83,84 Neither the cytoplasmic, transmembrane, spacer,
nor tether regions of KL (Fig 1) is
required for biological activity. Similar studies on FL have yielded
essentially identical results.85
View larger version (25K):
[in this window]
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| Fig 1.
Sequence alignment of human FL and KL proteins. The
figure illustrates that both colony-stimulating factors are type I
transmembrane proteins with short cytoplasmic domains; both are likely
to be four helix bundle proteins (based on x-ray crystallography data in the case of M-CSF82). The approximate positions of the
four helices are shown. The vertical red lines show the locations of
introns (to the nearest amino acid) within the
genes33,93,95,104 and illustrate their common genomic
structure and ancestral origin. Conserved cysteine residues are shaded
in color to reflect the formation of proposed intramolecular disulfide
bonds (3 in the case of FL and 2 in the case of KL). Possible sites for
N-linked glycosylation are boxed. The alignment is based on the one
originally proposed by Bazan78 for KL and M-CSF.
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The primary translation product of the FL gene is also a type 1 transmembrane protein. The mouse and human proteins contain 231 and 235 amino acids, respectively. The first 27 (mouse) or 26 (human) amino
acids constitute a signal peptide that is absent from the mature
protein, followed by a 161 (mouse) or 156 (human) amino acid
extracellular domain, a 22 (mouse) or 23 (human) amino acid
transmembrane domain, and a 21 (mouse) or 30 (human) amino acid
cytoplasmic tail. The cytoplasmic domains of murine and human FL are
only 52% identical and are much more divergent than the cytoplasmic
domains of murine and human KL (92% identical). Why the cytoplasmic
domains of mouse and human FL are so much more divergent in sequence
than the cytoplasmic domains of mouse and human KL is unknown. The
mouse and human FL proteins each contain two potential sites for
N-linked glycosylation. The human FL protein contains N-linked sugars
(Claudia Jochheim, Immunex; unpublished observation).
| |
KL AND FL ISOFORMS |
The mature mouse and human KL proteins (from which the amino acid
signal sequence has been cleaved) undergo proteolytic cleavage to
generate a soluble, biologically active, 164-165 amino acid protein.32,33,79,86 The primary site for proteolytic
cleavage is encoded within exon six33; however, mutagenesis
experiments have shown that there is a secondary proteolytic cleavage
site just upstream of the transmembrane region within exon
7.87 This secondary site is used only if the primary site
is missing, which can occur by splicing out the sixth
exon.79,88,89
Splicing has been suggested to be a method of regulating the generation
of soluble versus membrane-bound forms of the protein. Alternative
splicing of the sixth exon of the KL gene has been reported in both
mouse and human cells.40,79,88,90,91 The cell-bound form of
KL appears to be required for normal development in mice since a
mutation (Sld) that eliminates the membrane-bound
form of the factor, but still makes a biologically active soluble form,
results in developmental abnormalities.88,92 Huang et
al90 showed that there is tissue-specific expression of the
different isoforms. The physiologic significance of these altered
isoform ratios is unknown but presumably reflects the capacity of each
tissue to produce a form of KL that is capable of interacting with
specific c-kit-expressing cells.
It is unclear what regulates the proteolytic cleavage of KL, and what,
if any, the physiologic effects of this process are. The protease
responsible for cleavage of KL has not been identified, and it is
unknown if it is the same protease that generates soluble, biologically
active forms of M-CSF and FL.48,49,93
Multiple isoforms of both mouse and human FL have been identified by
analysis of multiple cDNA clones and PCR.48-50,94 The biological significance of these isoforms is presently unknown. The
predominant isoform of human FL is the transmembrane protein that is
biologically active on the cell surface.48-50 This isoform is also found in the mouse, although it is not the most abundant isoform in that species (see below). The transmembrane FL protein can
be proteolytically cleaved to generate a soluble form of the protein
that is also biologically active.48 Neither the protease responsible for this cleavage nor the exact site in the FL amino acid
sequence where cleavage occurs has been identified.
The most abundant isoform of murine FL95 is an alternative,
220 amino acid form that is membrane bound, but is not a transmembrane protein.49,94 This form arises due to a failure to splice
an intron from the mRNA. This leads to a change in the reading frame, which terminates in a stretch of hydrophobic amino acids that serve to
anchor the protein in the membrane.50 This isoform is
missing the spacer and tether regions that contain the proteolytic cleavage site seen in the transmembrane isoform. As a result, this
membrane-associated isoform is resistant to proteolytic
cleavage,94 although it is biologically active on the cell
surface. This isoform has not been identified in any human FL cDNAs
examined.
A third FL isoform identified in mouse94 and
human95 tissues arises because of an alternatively spliced
sixth exon. This exon introduces a stop codon near the end of the
extracellular domain and thereby generates a soluble, biologically
active protein that appears to be relatively rare compared with other
isoforms.95 Another method of generating soluble FL in the
human is to splice out the transmembrane domain,50 but the
relative abundance of this isoform has not been quantitated.
There is a difference between KL and FL in regard to their
alternatively spliced sixth exons. The amino acids in exon 6 of mouse
and human KL are nearly identical, whereas those of mouse and human FL
have virtually no homology.95 In the case of KL, the sixth
exon is normally part of the transmembrane protein and contains the
proteolytic cleavage site. In the case of FL, it is not a part of the
transmembrane protein; introduction of the sixth exon results in the
generation of a soluble protein due to a shift in the reading frame.
Thus, evolution has made two different uses of the sixth exon of KL and
FL, allowing the generation of a soluble protein by different
mechanisms.
| |
STRUCTURE OF THE GENOMIC LOCI ENCODING THE c-kit AND Flt3
RECEPTORS |
The genomic loci encoding the c-kit, flt3, and
c-fms receptors share overall conservation of exon size,
number, sequence, and exon/intron boundary positions,96 and
these genes have likely arisen from a common ancestral gene. The
genomic loci encoding the mouse97 and
human98-100 c-kit receptors show clear evidence of
evolutionary conservation. The coding region of the c-kit
receptor encompasses 21 exons, and both the mouse and human loci span
more than 70 kb of genomic sequence.
The human flt3 receptor genomic locus is approximately 100 kb in
size.101 The exon:intron structure of the entire receptor has been reported to contain 24 exons,102 but only the
portion of the gene encoding the C-terminal domain has been published.
| |
STRUCTURE OF KL AND FL GENOMIC LOCI |
The genomic locus encoding KL has been cloned from the
human,33 rat,33 and mouse.103 The
human KL locus is more than 50 kb in length (Vann Parker, Amgen,
Thousand Oaks, CA; personal communication) and consists
of eight exons that contain the entire coding region of the protein.
The intron:exon boundaries identified within the rat, human, and murine
genes occur at identical positions. In the case of the mouse protein, a
ninth exon is present and encodes the C-terminal end of the cytoplasmic
domain.103
The genomic loci encompassing the coding regions of mouse and human FL
are approximately 4.0 kb and 5.9 kb, respectively; the coding region
comprises 8 exons.95 The human FL locus is thus
significantly smaller than the human KL locus. The sizes of the
individual FL exons are well conserved between species,95 although the intron sizes are much more variable.
The genomic locus encoding M-CSF also contains eight
exons.104 A comparison of exon sizes between FL, KL, and
M-CSF shows that identically numbered exons are similar in size in all
three proteins.95 If the sizes of the exons are taken as a
measure of overall relatedness, then M-CSF and KL are more closely
related to each other than they are to FL. For example, the sizes of
exons 3 and 4 are identical between M-CSF and KL, but are not the same as the corresponding exons in FL. The location of the introns in the
three genes are also fairly well conserved, indicating that these
proteins are probably ancestrally related.
| |
CHROMOSOMAL LOCATION OF c-kit AND Flt3 RECEPTORS |
The murine c-kit locus is located in the D-E region of mouse
chromosome 511,12 near two other tyrosine kinase receptors
(PDGF A and flk-1/KDR). The murine flt3 receptor gene is also on
chromosome 5, but at the G region.41 The flt3
receptor105 is located less than 350 kb from the murine flt
tyrosine kinase receptor106 but is separated from the
clustered c-kit, PDGF A, and flk-1/KDR receptors.
The human c-kit locus is on the centromeric region of
chromosome 4, in the area of 4q31-34,53
4q11-21,54 and 4q11-12.107 The gene encoding
the human flt3 receptor maps to chromosome 13q12,41 again
near the flt receptor locus. The flt3 and flt genes are linked105 in a head to tail fashion and are separated by
about 150 kb.101
| |
CHROMOSOMAL LOCATION OF KL AND FL GENES |
The KL gene is, as expected, encoded on mouse chromosome 10 and is
deleted in some, but not all, Sl alleles.32,35,36
The FL gene maps to the proximal portion of mouse chromosome
7.94
The gene encoding human KL has been mapped to chromosome
12q22-2440 and 12q14.3-qter108 in a region that
is syntenic with mouse chromosome 10. The human FL gene maps to
chromosome 19q13.3-13.4,94,109 which is syntenic with mouse
chromosome 7. The chromosomal locations of KL, FL, M-CSF, and their
receptors are summarized in Table 1.
| |
GENETIC ALTERATIONS IN c-kit AND KL GENES |
The exact defect in the c-kit receptor has now been identified
at the molecular level for a number of alleles of the W
locus.24-28 Most of the alleles result from point mutations
in the cytoplasmic domain of the receptor; these changes decrease the
tyrosine-phosphorylating activity of the protein. However, in several
cases, the mutations appear to be of a regulatory instead of a
structural nature and result in reduced expression of the c-kit
receptor.
There is a rare, autosomal dominant genetic disease in humans known as
piebald trait. Affected individuals have a white forelock and large,
nonpigmented patches on the chest and/or other areas. All cases
of piebald trait that have been molecularly analyzed result from
missense or frameshift mutations in the c-kit tyrosine kinase
receptor (Ezoe110 and references therein). Affected
individuals are heterozygous for defects in the c-kit protein;
the dominant nature of the trait reflects the dominant-negative effects
of the mutant c-kit allele. The dominant-negative effects of
these mutations are thought to result because receptor dimerization is
required for proper biological function.
Because pigmentation defects in W and Sl mice are often
indistinguishable, it would be reasonable to expect that at least some
cases of piebald trait in humans would arise from mutations in the KL
gene, ie, from a defect in the ligand instead of the receptor. However,
no defects in the KL gene have been reported in piebald humans. Piebald
trait thus represents the human homologue of the W mutation in
mice.
Mutations at the Steel locus35 have occurred spontaneously
or have been induced by chemical mutagenesis, x-ray irradiation, or
transgene insertion.111 In addition to the
Sld mutation (see above), the molecular defect
responsible for three other Sl mutations has been identified.
In the Sl17H mutation,103 the
cytoplasmic tail of KL is altered as a result of a splicing defect; in
contrast, the Slcon and Slpan
mutations are of a regulatory nature and result in altered,
tissue-specific expression of mRNAs encoding KL.112
| |
GENETIC ALTERATIONS IN Flt3 RECEPTOR AND FL GENES |
In contrast to the well-described mutations in the c-kit
receptor and its ligand (see above), there are no reports of any genetic defects associated with either the flt3 receptor or its ligand.
As described above, FL maps to human chromosome 19q13.3. Trisomy 19 is
strongly associated with myeloid malignancies.113 However,
whether overexpression of FL plays a role in the increased incidence of
leukemia in trisomy 19 remains to be determined.
| |
EXPRESSION OF KL AND FL IN MOUSE AND HUMAN HEMATOPOIETIC TISSUES |
The expression of the c-kit and flt3 receptors, and not their
ligands, is the key to understanding the function of these growth factors. Numerous studies have shown that both KL and FL are widely expressed in different tissues, in contrast to their receptors, which
are expressed on a more limited number of cells, especially in the case
of flt3. KL is widely expressed during
embryogenesis,114-116 suggesting that KL may affect the
growth, survival, and/or differentiation of cells in addition
to the three lineages (hematopoietic cells, germ cells, and
melanocytes) shown to be affected in both W and Sl
mutant mice. Cells expressing KL are frequently contiguous with cells
expressing c-kit, ie, ligand and receptor expression are
complementary. KL is expressed on stromal cells,117,118
fibroblast,26,79,119 endothelial cells,117
visceral yolk sac,115 and other places.
FL, like KL, is widely expressed in both murine and human
tissues.49,50,94 Highest levels of FL mRNA on human tissue
Northern blots are in peripheral blood mononuclear cells, but the
ligand is also expressed in almost every tissue that has been
examined.48-50 Mouse developmental in situ hybridization
studies have not yet been performed with FL, although it would be
interesting to see how the distribution of FL would compare with flt3
receptor.120
| |
EXPRESSION OF c-kit AND Flt3 RECEPTORS ON HEMATOPOIETIC CELL
LINES |
Expression of the c-kit receptor has been extensively surveyed
on mouse and human hematopoietic cell lines
(Table 2). It is seen on only a small
percentage of myeloid and myeloblastic cell lines.121-124
In contrast, the majority of erythroid and erythroleukemia cell lines
express c-kit,121-123,125 as do virtually all
megakaryocytic cell lines.121,123,125 Mast cell lines
generally express c-kit.51,126-128 In contrast,
expression of c-kit is generally not seen on lymphoid leukemia
cell lines (including pre-B, B, and T cells),121,123,125 on
B-cell or T-cell lymphoma cell lines,121,122,125 or on
myeloma cell lines.121
Flt3 receptor expression on mouse and human cell lines is quite
different from that of c-kit. No flt3 expression is seen on any
of the mouse myeloid, macrophage, erythroid, megakaryocyte, or mast
cell lines examined46,129 or most early mouse B-cell lines,
but it has been reported on several mature B-cell lines.129 This lack of expression is different from what is seen on most human
pre-B-cell lines, which do express flt3 receptor.123,130 In
addition, flt3 expression has been seen on only one mouse pro-T cell
line, but not on any T-cell lines.46,129
A number of studies have been published that show expression of flt3
receptor on a limited range of human cell lines. The flt3 receptor is
found on a high percentage of human myeloid and monocytic cell
lines,123,129,130 in contrast to mouse cell
lines.46,129 No flt3 expression is seen on myeloma cell
lines,129,130 and only a few megakaryocytic cell lines are
positive.123,129,130 All erythroid and erythroblastic cell
lines are flt3 negative as well.129,130
Among lymphoid cell lines, pro-B as well as pre-B lines are flt3
receptor positive,129,130 whereas natural killer (NK) cell lines and Hodgkin's cell lines are negative,130 as are all
T-cell lines.123,129,130
| |
EXPRESSION OF c-kit AND Flt3 RECEPTORS ON PRIMARY HUMAN
LEUKEMIAS |
Both the c-kit and flt3 receptors are frequently seen on acute
myelogenous leukemia (AML) blasts. The c-kit protein is
expressed on blast cells obtained from a high percentage of patients
with AML from all French-American-British (FAB)
subtypes.61,124,131-139 Receptor levels on AML blast cells
are variable, but in general are similar to or less than c-kit
levels on normal stem and progenitor cells.140
Expression of the flt3 receptor in primary leukemias has also been
investigated and recently reviewed.141 As with
c-kit, the majority of adult AML samples from all FAB classes
are positive for flt3 receptor expression.57,142-146
Among lymphoid leukemias, little or no expression of c-kit is
observed on blast cells in acute lymphoblastic leukemia
(ALL).133,143 c-kit is expressed on Reed-Sternberg
cells in about half of Hodgkin's disease patients as well as on some
anaplastic large-cell lymphoma samples.147
All B-lineage ALL samples examined are flt3 receptor
positive,142-144 as are most hybrid (also known as mixed or
biphenotypic) leukemia samples.144 The greatest variability
reported in flt3 receptor expression is on T-lineage ALL, which have
been reported to be all negative,142 have a small
percentage that are positive,143 or have about half of the
samples positive.144 In contrast, both T-cell and B-cell
lymphomas are negative for flt3 receptor expression.144 Tandem in-frame duplications in the juxtamembrane region of the human
flt3 receptor have been reported to be associated with both leukocytosis148 and leukemic transformation.149
The c-kit receptor is expressed on a majority of samples from
chronic myelogenous leukemia (CML) patients in blast
crisis134,150 and at least some samples of chronic phase
CML138 and CML in blast transition.151 In
contrast, almost all chronic-phase or accelerated-phase CML samples are
negative for flt3 receptor expression.143,144 However,
about two thirds of the samples from CML patients in blast crisis are
flt3 receptor positive.143,144
| |
RESPONSIVENESS OF PRIMARY LEUKEMIA CELLS TO KL AND FL |
AML.
Numerous studies have been performed on human leukemia samples to
determine whether the cells proliferate in response to KL, FL, or other
growth factors, although a lack of proliferation should not necessarily
be considered negative expression. For example, a growth factor could
drive differentiation or inhibit apoptosis; in fact, both
KL152 and FL153 have been shown to have this
latter effect. In the case of nonproliferative cells, the cells may be
truly nonresponsive or may be producing endogenous ligand, and thus are
refractory to exogenously added growth factor.
c-kit receptor expression is variable among AML FAB subtypes
and does not predict responsiveness to KL.145 The
majority of AML samples proliferate in response to
KL.61,131,137,154,155 Many of these studies show that
KL synergizes with other cytokines to enhance the proliferation of
leukemic blast cells. Some AML cell lines express KL in addition to
c-kit,140,156 suggesting that an autocrine loop may
play a role in the transformation of these cells. However, the low
level of KL expression on some AML cells has led one group to conclude
that a c-kit and KL autocrine cycle is not common in
AML.140
Whether flt3 receptor or its ligand play a causal role in the
development of human leukemias has not been determined. A large percentage of AML cells from children142 and
adults145,146 proliferate (as measured by both
[3H]-thymidine incorporation or colony formation) in
response to FL. Within age groups (children or adults), some FAB
subtypes show a greater response compared with
others.142,146 It is unclear whether there is a difference
in the FL responsiveness of flt3 receptor-positive AML samples of
different FAB subtypes from children and adults because not enough
samples of each FAB subtype have been analyzed.
Primary AML samples that proliferate in response to FL also frequently
proliferate in response to granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and KL, and additive or synergistic responses are observed. Some AML cells are therefore similar to normal hematopoietic progenitor cells in that both show
synergistic responses to FL in combination with other cytokines. Many
of the AML samples that do not proliferate in response to FL do
proliferate in response to other cytokines,142 indicating that the cells do not lack a general capacity to proliferate. In
summary, flt3 receptor expression on AML samples is not predictive of
FL responsiveness, just as c-kit expression is not predictive of KL responsiveness.
CML.
KL can weakly stimulate the proliferation of CML blast cells on
its own and strongly stimulate them in the presence of IL-3 and/or GM-CSF.138 Culturing of bone marrow (BM)
cells from CML patients in the presence of KL favors the growth of
malignant progenitor cells.157 In contrast, preliminary
results suggest that FL favors the outgrowth of benign progenitors from
5-FU-treated CD34+ CML BM cells at the expense of malignant
cells158 and that FL generates a significantly greater
percentage of normal progenitors (Philadelphia chromosome-negative
cells) compared with KL.
ALL.
Because c-kit is not generally expressed on ALL
cells,124,133,134,139 the capacity of these cells to
proliferate in response to KL has not been examined. As mentioned
above, all B-lineage ALL and some T-lineage ALL samples express flt3
receptor. However, only a small percentage of B-lineage ALL samples
proliferate in response to FL.142
In one study, pediatric T-lineage ALL samples did not proliferate in
response to FL, but none of these samples was positive for flt3
expression.142 In a separate study on a variety of ALLs, several flt3 receptor-positive samples proliferated in
FL.159 However, the majority of samples failed to
proliferate in FL, even though they were flt3 receptor
positive.159 Flt3 receptor expression is therefore not
predictive for proliferation of ALL cells to FL in vitro.
| |
EXPRESSION AND FUNCTION OF c-kit AND Flt3 IN THE
HEMATOPOIETIC HIERARCHY |
Studies of cytokine receptor expression have proven valuable in
pinpointing where specific ligand-receptor pairs have biological activities. Not only can such studies identify cell types in which a
specific receptor might be important, they also allow functional characterization of distinct cell populations separated based on
various levels of receptor expression. The expression of c-kit and flt3 in the hematopoietic system has been studied in detail, and in
the following sections we review the findings of flt3 and c-kit
expression on various cell types (summarized in
Fig 2), followed by the in
vitro biological effects (summarized in
Table 3) of FL and KL on the same cell
types. It is important to emphasize that the extensive c-kit
and flt3 expression studies to be described have inherent limitations.
Most expression studies have been performed by flow cytometric
evaluation of cell-surface c-kit and flt3 expression. Because
flow cytometry has a rather high detection limit (~500 molecules/cell), so- called c-kit and
flt3 populations might prove to express low levels of
c-kit and flt3, respectively. On the other hand, reverse
transcriptase-PCR (RT-PCR) detection of c-kit
and flt3 mRNA has much greater sensitivity, but unless performed at the
single-cell level does not provide a quantitative measurement of
c-kit+ and flt3+ cells. Thus, a minor
contaminating (nonrelevant) cell type might account for detected
expression (particularly relevant for heterogenous primary cell
populations).
View larger version (43K):
[in this window]
[in a new window]
| Fig 2.
c-kit and Flt3 expression in the hematopoietic
hierarchy. The figure indicates expression of c-kit (red, upper
symbol on side of each cell) and flt3 (green, lower symbol on side of
each cell) on various classes of hematopoietic stem and progenitor
cells as well as mature blood cells, as described in the text. Because most hematopoietic cell populations are heterogeneous and hard to
purify, it is not possible to exclude c-kit and/or flt3
expression on a minority of cells in the different cell populations.
Therefore, the figure illustrates the c-kit and flt3 receptor
status on the majority of cells within a specific population, based on
studies of receptor expression and/or functional studies. As
discussed in the text, the proposed hierarchy of pluripotent stem cells is based solely on different levels of c-kit and flt3
expression and does not take into account other stem cell
antigens/characteristics, which are likely to uncover additional
heterogeneity. Symbols: ( ) most/all cells appear to lack
c-kit or flt3 expression; (+) most/all cells appear to
express c-kit or flt3; (+/) the cell type appears to
consist of significant receptor-positive as well as receptor-negative
populations; (?) sufficient expression or functional data not
available; (high and low) cell populations have been separated based on
high and low levels of c-kit expression. Abbreviations:
BFU, burst-forming units; CFU, colony-forming units; E, erythroid; Mk,
mega karyocyte; G, neutrophilic progenitor; M, monocyte/macrophage; DC,
dendritic cell; Baso, basophil; RBC, red blood cell; NK, natural killer
cell.
|
|
| |
EXPRESSION OF c-kit AND Flt3 ON MATURE BLOOD CELLS |
c-kit and flt3 expression in the hematopoietic system appear
predominantly restricted to the progenitor/stem cell compartment (outlined in the following sections). However, some differentiated blood cells also express these receptors (Fig 2).
c-kit is expressed on primary mast cells as well as mast cell
lines and primary neoplastic mast cells.160 In addition,
c-kit is constitutively activated in a number of mast cell
tumor lines (mastocytomas),127,161 but mast cells do not
express flt3.128
There are other differentiated hematopoietic cells that express
c-kit and/or flt3, although the functional significance
is less clear. In mouse BM, very low levels of
c-kit can be detected on promyelocytes and myelocytes, but not
on neutrophils.162 Approximately 50% of murine BM
eosinophils and monocytes express low levels of
c-kit.162 Seven percent of lymphocytes in murine BM
express high levels of c-kit.162 However, still
other studies suggest that mature B and T cells do not express
c-kit; therefore, this small fraction of
c-kit+ cells might represent B- and T-cell
precursors/progenitors.163-165
Similar studies have revealed that flt3 expression in murine BM is
restricted to blast cells, monocytes, and a small fraction of
lymphocytes.166 Nucleated murine erythroid cells lack both c-kit and flt3 expression.162,166 Early murine
megakaryocytes (stage I and II) express c-kit, whereas the most
mature (stage III) megakaryocytes appear to be
c-kit.167 Also, human
megakaryocytes express c-kit,61,168 but not flt3.169 In addition, activated but not resting platelets
express c-kit.170
Initial studies indicated that flt3 mRNA is expressed by murine B and T
cells from thymus, spleen, and peripheral blood.18 However,
several later studies of mature murine B and T cells suggest that these
do not express flt3.166,171 Thus, the initial findings
potentially were due to a small fraction of contaminating flt3+ cells, such as more primitive B- and T-cell
progenitors.
Peripheral human blood cells contain less than 0.1%
c-kit+ cells, suggesting that very few mature human
blood cells express c-kit.172-174 c-kit is
constitutively expressed on a small subset of resting human NK cells in
peripheral blood that are characterized by high CD56 expression,
whereas c-kit is not expressed on the larger fraction of more
differentiated NK cells with low CD56 expression.175 These
c-kit+ NK cells appear to be the only mature,
resting lymphocytes that constitutively express c-kit.
No expression of flt3 mRNA has been reported on mature
lympohematopoietic cells fractionated from human peripheral
blood17 or B cells, T cells, monocytes, or
granulocytes.144 However, in other studies, monocytes and
granulocytes have been shown as weakly positive at the mRNA and
cell-surface level.16,176
| |
RESPONSE OF MAST CELLS TO KL, BUT NOT FL |
The effects of KL on mast cell populations have been extensively
reviewed6 and will be only briefly summarized here. KL regulates the migration, maturation, proliferation, and activation of
mast cells in vivo.6 Injection of recombinant KL into
rodents,86,177 primates,178 or
humans179 results in an increase in mast cells at both the
site of injection and at distant sites. Treatment of rats with KL
generates both connective tissue mast cells and mucosal mast
cells.177 Animals treated with KL generally do not appear
to suffer from serious adverse events despite the large-scale expansion
of mast cells in vivo.178 However, at least one study has
shown that KL administration to mice leads to degranulation of mast
cells in the lungs, which leads to acute respiratory
distress.180 The effects of KL on mast cells may have a
significant impact on the clinical potential of this molecule for
humans.179,181,182
In contrast to c-kit, flt3 is not expressed on primary mast
cells or mast cell lines, and these cells, not surprisingly, do not
respond to FL.51,128 This lack of flt3 expression on mast cells is one of the key differences between KL and FL.
| |
COMMITTED MYELOID PROGENITOR CELLS ARE
c-kit+Flt3+ OR
c-kit+Flt3, WHEREAS EARLY ERYTHROID
PROGENITOR CELLS APPEAR TO BE ONLY
c-kit+Flt3 |
Half of c-kit+ murine BM cells coexpress
lineage-specific cell surface antigens such as GR-1 and MAC-1
(Lin+), characteristic of cells committed to the myeloid
lineage, whereas the remaining half express higher levels of
c-kit and are Lin, suggesting that uncommitted
progenitor cells might express higher levels of c-kit than
those committed to the myeloid lineage.183 Indeed, murine
in vitro clonogenic progenitor cells committed to the myeloid lineage
and colony-forming units-spleen (CFU-S) progenitors are almost
completely depleted in c-kit BM cells,
showing that most, if not all, clonogenic myeloid progenitor cells
express c-kit.183-188
Most c-kit+ human BM and fetal liver cells express
the progenitor-associated CD34 antigen,172-174 suggesting
that overlapping (but not identical) populations each express these two
progenitor cell antigens. c-kit+ human BM and fetal
liver cells are highly enriched and contain all or most in vitro
clonogenic progenitor cells with a myeloid (granulocyte/monocyte),
megakaryocytic, and/or erythroid
potential.172-174,189
CD34highCD64+ cells, which are virtually a pure
population of human GM progenitor cells, express high levels of
c-kit, whereas the more mature
CD34lowCD64+ cells express lower levels of
c-kit,190 suggesting downregulation of
c-kit expression during GM differentiation. Similarly,
erythroid progenitor cells
(CD34highCD64CD71high and
CD34lowCD64CD71high) also
express high levels of c-kit.190 Although some
studies have suggested that a subclass of mature erythroid progenitor cells (colony-forming units-erythroid [CFU-E]) might
not be KL-responsive, c-kit expression has been demonstrated on
human CFU-E and erythroblasts.174 The vast majority of
human megakaryocyte progenitor cells (burst-forming unit-megakaryocyte
[BFU-Mk] as well as colony-forming unit-megakaryocyte [CFU-Mk]) are also
c-kit+.191
Whereas almost 90% of murine BM blast cells express
c-kit,162 flt3 expression is restricted to 30% of
murine BM blast cells.166 The majority of
lineage-restricted murine myeloid and erythroid BM progenitor cells are
LinSca-1 and express
c-kit.188 However, less than half of these
LinSca-1c-kit+
progenitors express flt3.166
More than 60% of flt3+ human BM cells coexpress CD33, a
myeloid cell-surface antigen, suggesting that flt3 might be expressed on subsets of myeloid progenitor and/or mature
cells.57 Most human CD34+ BM and cord blood
cells express flt3, and most GM progenitors express flt3, whereas
CD34+flt3+ cells are depleted in erythroid
progenitors.176 The majority of
CD34+c-kit+ BM and cord blood cells
coexpress flt3, but a significant (10% to 25%) population is
flt3.
Flt3 appears to be shut off before erythroid differentiation and
gradually downregulated during GM differentiation.192 In contrast, c-kit expression is gradually downregulated during
both erythroid and GM differentiation.192 Thus, flt3
appears to be expressed on subpopulations of myeloid (GM) progenitor
cells, but not on erythroid progenitor cells.
Myeloid-derived dendritic cell (DC) progenitors appear to express
c-kit and flt3, because they respond to KL and FL in
combination with other cytokines (see DC section for details). However,
neither ligand has been shown to have effects on mature
DC.193-196
| |
ERYTHROID PROGENITOR CELLS: KEY ROLE OF KL AND ABSENCE OF FL
RESPONSE |
Besides the mast cell deficiency, the dominating hematopoietic defect
resulting from severe mutations in the W or Sl loci is
a macrocytic anemia.6,10 KL enhances the in vitro cloning frequency as well as the clonal size of murine79,197 and
human33,172,174,198-200 erythroid progenitor cells. KL has
its most potent growth promoting effects on early erythroid progenitor
cells (BFU-E), whereas more mature progenitors (CFU-E) are less
responsive to KL-stimulation.172-174,191,201
The effects of KL on the growth of BFU-E are predominantly synergistic
and require costimulation with erythropoietin
(EPO).79,172,174,197-200 However, KL can, in combination
with IL-6 and soluble IL-6 receptor, promote EPO-independent growth of
human BFU-E in vitro.202 Furthermore, c-kit might
activate the EPO receptor by inducing its phosphorylation on
tyrosine.203 KL also promotes the adhesion of human BFU-E to fibronectin.204
In contrast, FL appears to have little or no effect on
murine205,206 and human49,50,192,207,208
erythropoiesis in vitro. This is in agreement with the observed lack of
flt3 expression on normal erythroid progenitor cells166,192
as well as erythroleukemic cell lines.123,130
| |
MEGAKARYOCYTE PROGENITOR CELLS: POTENT GROWTH-PROMOTING EFFECTS
MEDIATED THROUGH c-kit BUT NOT Flt3 |
Although Sl/Sld mice have normal levels of
platelets, their BM displays reduced numbers of mature megakaryocytes
and megakaryocyte progenitor cells.209-211 Administration
of KL to Sl/Sld mice not only reverses the
macrocytic anemia, but results in enhanced platelet
production.36 In vitro, KL enhances megakaryocyte progenitor cell cloning frequency and growth potential in combination with other cytokines, including GM-CSF, IL-3, IL-6, and
IL-11.168,212-215 Whereas some studies have found little or
no effect on megakaryocyte maturation and ploidy, others have suggested
that KL can promote megakaryocyte maturation and ploidy,216
and subsets of early megakaryocytes express
c-kit.167
Thrombopoietin (TPO) is the primary regulator of megakaryocyte and
platelet production,217 and KL appears to interact with TPO
at two levels in the hematopoietic hierarchy. First, a synergistic interaction is observed on committed megakaryocyte progenitor cells,
enhancing megakaryocyte production.217-221 In
addition, KL and TPO interact synergistically on candidate murine and
human stem cell populations to stimulate multilineage growth in
vitro.222-226 Thus, the primary role of KL in platelet
production might be through its interaction with TPO.
Unlike W/Wv and
Sl/Sld mice, flt3 knockout mice have not
been reported to have any defects in megakaryocyte and platelet
production,227 and FL alone or in combination with IL-3,
KL, or TPO has no effect on in vitro growth of murine megakaryocyte
progenitor cells.65 Similarly, FL has no effect on
megakaryocyte ploidy by itself or in combination with
TPO.65 In contrast, FL acts synergistically with TPO to
enhance the growth of candidate murine stem cells.223
Some data suggest that FL might have effects on human
megakaryocytopoiesis. Some megakaryocytic leukemic cell lines, as well as primary megakaryoblastic leukemic cells, express flt3, although less
frequently than c-kit.65,123,130 In addition,
studies of FL effects on primary BM cells have demonstrated effects on
megakaryocyte formation.228 Unlike KL, FL has been reported
to have no synergistic interaction with TPO on in vitro clonogenic
growth of human megakaryocyte progenitor cells.169 Thus,
the finding that FL and TPO synergistically promote prolonged
megakaryocyte progenitor cell formation in long-term cultures of human
CD34+ cord blood cells229 could result from a
recruitment of primitive (uncommitted) progenitor cells that might
subsequently become responsive to TPO alone.
| |
EXPRESSION OF c-kit AND Flt3 ON LYMPHOID PROGENITORS AND
PRECURSORS |
About 25% of B220+ murine BM cells express c-kit,
accounting for more than half of the total c-kit+
cells.164 However, no BM cells (or fetal liver cells)
expressing cytoplasmic µ coexpress c-kit, suggesting that
c-kit expression is restricted to the earliest stages of B-cell
progenitors, whereas the pre-B-cell and subsequent stages are
c-kit.163,164,230,231
Flt3 mRNA is expressed in early murine pre-pro and pro-B cells, whereas
pre-B cells, as well as immature and mature B cells, are devoid of flt3
expression.171 A similar pattern of flt3 expression is seen
at the cell surface of pro-B, pre-B, and mature B cells.166 c-kit is also expressed at low levels on subsets of human pro-B cell progenitor cells
(CD34+CD19+).173,189,190
Twenty-five percent of BM CD34+CD19+ (pro-B
cells) express flt3, as do subfractions of CD10+ and
CD20+ B-cell precursors.176
c-kit is expressed at high levels on the most primitive subsets
of murine fetal and adult thymocytes, including
CD4CD8CD3CD44+CD25+
pro-T cells and more primitive
CD4loCD8CD3 thymocytes, the
latter cells also having the potential to develop into B
cells.165,232-235 When thymocytes develop into
CD4CD8CD3CD44CD25+
pre-T cells, they still express low levels of c-kit, which is lost in later stages of T-cell development.165
Like c-kit, flt3 expression is restricted to the most immature
CD4CD8 murine thymocytes, whereas more
mature thymocytes expressing CD4 and/or CD8 are
flt3.19
Because human NK cell progenitor cells respond to KL or FL (see
separate section), they most likely express c-kit and flt3. However, there is as yet no direct evidence for c-kit or flt3 expression on NK cell progenitor cells, and the few human NK cell lines
examined lack flt3 expression.130,236
Multipotent lymphoid progenitor cells capable of producing DC express
high levels of flt3.237 Because a DC-restricted lymphoid progenitor has not yet been identified, c-kit and flt3
expression on such a CFU-DC remains to be established.
| |
EARLY B-CELL DEVELOPMENT: COEXPRESSION OF c-kit AND Flt3
AND APPARENT KEY ROLE OF Flt3/FL INTERACTION |
Although no reduction in cells of the B-cell lineage has been reported
in adult W mutant mice, embryonic mice deficient in c-kit or KL expression have reduced numbers of B-cell
progenitor cells in fetal liver.238 Such a reduction could
indicate a direct role of c-kit and its ligand in B
lymphopoiesis or, alternatively, an indirect effect of a depleted pool
of pluripotent stem cells and/or altered stromal cells in these
mice.186
KL can synergize with IL-7 to promote stroma-independent growth of
murine BM pro-B- and pre-B-cell progenitors unresponsive to IL-7 alone,
whereas KL lacks proliferative activity on
B220+cµ+ pre-B
cells.33,118,239,240 One study found that KL in combination with IL-7 could promote development of pre-B cells and expression of
µ-heavy chain118; other studies have not found KL plus
IL-7 sufficient to allow differentiation of pro-B cells into pre-B
cells in vitro, even though such pro-B cells coexpress c-kit
and IL-7 receptors.231,239,240 Furthermore, a blocking
antibody against c-kit inhibits the growth of murine pro-B
cells cultured on stromal cells in the presence of IL-7, but has no
effect on pre-B-cell differentiation supported by the same stroma
cells.163,241,242 Similarly, KL in combination with IL-7
can replace the requirement for stroma to induce pro-B-cell proliferation, but not differentiation into pre-B cells.239
In addition to its ability to promote growth of committed pro-B cells, KL in combination with IL-7 can stimulate stroma-independent B-cell progenitor cell development from candidate murine stem
cells243-245 or from bipotent macrophage-B-cell progenitor
cells.246
In vivo treatment of mice with a blocking antibody against
c-kit results in an almost complete elimination of myeloid and primitive hematopoietic progenitor cells, leaving virtually no mature
granulocytes and erythroblasts in the BM.164,183 However, the total number of BM cells are normal, of which the majority are
B220+.164,183 A concomitant expansion in the
number of pre-B-cell progenitor cells is observed,164,183
suggesting that an interaction between c-kit and KL is not
required for B-cell development in vivo. In support of this, W/W
stem cells are as efficient as wild-type stem cells at
reconstituting BM B cells in RAG-2-deficient mice.247 Thus,
unlike the critical role of c-kit/KL interaction in generation of the erythroid, myeloid, and T-cell lineages, c-kit-KL is not required for normal B-cell development in adult mice. The mechanism behind the intriguing observation that a c-kit antibody blocks the production of mature myeloid and erythroid progeny but enhances B-cell development remains unclear, although it appears to result from
an indirect rather than a direct effect.
An important and distinct role of FL in early stages of B-cell
development is supported by studies of flt3-deficient mice. These
animals, unlike c-kit-deficient mice, have reduced numbers of
pro-B cells in the BM, although the number of mature B cells is
normal.227 These findings have also been confirmed in
FL-deficient mice.248
FL promotes the in vitro growth of early B-cell progenitor cells in a
pattern distinct from that of KL. Primitive
(CD43+B220lowCD24) B-cell
progenitors in murine BM do not respond to either FL or IL-7
individually, but in combination the two cytokines induce a greater
proliferative response than IL-7 plus KL.249 In contrast, more differentiated CD43+B220lowCD24+ B-cell progenitors fail to respond to FL, whereas KL
enhances IL-7-induced proliferation, indicating that FL activity is
restricted to an earlier stage of B-cell development than KL activity.
Another important finding is the capacity of FL plus KL to promote the growth of CD43+B220lowCD24
B-cell progenitor cells in the absence of IL-7.249 This
might help explain why IL-7 receptor-deficient mice have normal levels of these primitive B-cell progenitors, but dramatic reductions in more
differentiated B-cell progenitors and mature B cells.250 It
could also explain why mice with a combined deficiency in flt3 and
c-kit have a more severe reduction in early B-cell progenitors than mice deficient in flt3 only.227
FL synergizes with IL-7 to enhance the production of B220+
cells from B220+ as well as B220 murine BM
cells.245 IL-7-independent B220+ cell
development occurs in the presence of FL alone, but not KL alone,
indicating a primary role of FL over KL in early murine B-cell
development. Pro-B cells isolated from murine fetal liver also
proliferate in response to either FL or KL in combination with IL-7,
maintaining a population of early pro-B cells.251
Because the B-cell defect in flt3-deficient mice is restricted to a
reduction in the most primitive B-cell progenitors, an essential role
of flt3/FL might be to promote B-cell development from progenitor/stem
cells not yet committed to the B-cell lineage. In support of this, FL
and KL can each promote the growth of fetal liver and BM progenitor
cells with a combined myeloid and lymphoid potential.251,252 FL and IL-7 synergize to enhance the
growth of primitive murine LinSca-1+ BM
progenitors, resulting in production of almost exclusively pro-B cells,
whereas KL plus IL-7 stimulate formation of 90% myeloid cells.252
Studies of the early stages of human B-cell growth have been hampered
by the lack of optimized in vitro systems. Therefore, the potential
roles of KL and FL in human B-cell development remain to be elucidated.
A stimulatory effect of KL on committed human B-cell progenitors has
been suggested,253 although stromal and IL-7-dependent
early B lymphoid growth from BM or cord blood cells in vitro is neither
stimulated by KL nor inhibited by a neutralizing anti-KL
antibody.254-256 In contrast, FL in combination with IL-7 promotes stromal cell-independent growth of human fetal BM pro-B cells
(CD34+CD19+), whereas KL has no
effect.256
Although the precise roles of FL and KL in B lymphopoiesis remain to be
determined, the available in vitro, in vivo, and knockout data suggest
that flt3 and FL may be more critically involved in early B-cell
development than c-kit and KL, perhaps identifying a
physiologically important difference between KL and FL.
| |
T-CELL PROGENITOR CELLS |
In mice lacking functional c-kit expression, T-cell numbers in
peripheral blood are normal,257 although a deficiency in
fetal thymic development has been reported.258
One purified c-kit+ BM stem cell can reconstitute
the thymus in more than 40% of sublethally irradiated mice, whereas
c-kit stem cells have little or no such
ability.259 Although the BM population can produce
myeloid/erythroid as well as T-cell progeny, thymus-derived
c-kit+LinThy-1lo cells
appear to be lymphoid-restricted.260 Anti-c-kit
antibodies completely block T-cell generation from BM, but not thymic
cells, suggesting that T-cell generation from these primitive,
lymphoid-committed stem cells in the thymus might not require signaling
through c-kit.260
KL has little or no growth-promoting activity alone, but promotes
IL-7-stimulated growth of primitive mouse
CD4CD8CD3 thymocytes, but
not CD4+CD8+ cells or single CD4+
and CD8+ cells.234,261 Anti-c-kit
antibodies dramatically inhibit in vitro fetal thymic T-cell production
and differentiation from fetal liver progenitor cells.234
Similarly, anti-c-kit antibodies reduce cell production and
differentiation towards CD4+CD8+ cells in a
reconstitution assay with fetal thymocytes into fetal thymus.232 This suggests that KL might be involved in
promoting the growth and differentiation of immature thymocytes. IL-3
and IL-12 have been shown to synergize with KL to enhance the growth of
primitive, but not more mature, thymocyte populations.235
T-cell numbers in peripheral blood are normal, but a reduction in early
T-cell progenitors is seen postnatally in flt3-deficient mice, and
flt3-deficient stem cells are impaired in their ability to reconstitute
T cells in the thymus and peripheral blood.227
FL synergizes with IL-7 to stimulate the proliferation of
unfractionated murine thymocytes, and a stimulatory effect can be seen
in response to FL in the absence of IL-7.49 The most
primitive CD4low thymic progenitor cells capable of
generating multiple lymphoid lineages are growth stimulated by FL (in
combination with IL-3, IL-6, and IL-7) more efficiently than with
KL.262 In contrast, pro-T cells are more efficiently
expanded with KL than FL, suggesting that FL might be more active than
KL at an earlier stage of T-cell growth.262 In agreement
with this, FL appears to preferentially promote self- renewal of
CD4low cells in fetal thymic organ culture, whereas KL
promotes early T-cell differentiation.262
Studies of cytokine effects on the regulation of human T-cell
development have been difficult due to the lack of appropriate in vitro
assays. However, KL enhances thymic stromal cell-supported production
of human CD4+ and/or CD8+ cells from
CD34+CD4CD8 BM progenitor
cells,263 whereas FL promotes IL-12-stimulated T-cell
production from human CD34+ BM cells on thymic stromal
layers.264
| |
NK CELL PROGENITORS |
c-kit is constitutively expressed on a small subset of resting
human NK cells in peripheral blood characterized by high CD56 expression, but not on the larger fraction of more differentiated NK
cells with low CD56 expression.175 These c-kit
receptors are functional because KL suppresses apoptosis, apparently
through induction of bcl-2 expression, although it does not promote
proliferation, differentiation, or cytotoxicity on its
own.152,175 However, KL in combination with IL-2 promotes
the growth, but not cytotoxicity, of this population of resting NK
cells.175
KL enhances stroma-independent NK cell development from human BM
progenitor cells stimulated by IL-2, IL-7, or IL-15 in
vitro.265-267 An important regulatory role of flt3 and its
ligand in NK cell development is supported by the finding that
FL-deficient mice treated with poly IC or IL-15 are devoid of NK
cell activity in the spleen.248 Furthermore, FL in
combination with IL-15 promotes the expansion but not differentiation
of CD3CD56+ NK cells from human
CD34+ progenitor cells.268
| |
DC DEVELOPMENT: KEY ROLE OF FL |
All DC express CD45 and arise from BM progenitor cells; evidence
suggests that DC derive from myeloid and lymphoid progenitor cells.269,270 Myeloid-derived DC can be generated in vitro
from progenitor cells isolated from BM, mobilized peripheral blood, or
cord blood; GM-CSF appears to play a primary role in promoting their
production.269,270 A number of cytokines, including tumor necrosis factor- (TNF-), IL-4, and KL, can enhance DC formation induced by GM-CSF.269,270 KL stimulates DC formation from
human CD34+ BM and cord blood progenitor cells in
combination with GM-CSF and TNF- without affecting DC
differentiation.193-195
FL increases the production of DC from CD34+ BM progenitor
cells in combination with GM-CSF plus TNF plus IL-4.196
This enhanced DC production is similar to that observed in response to
KL, and when these two cytokines are combined, the effect is
additive.196 As with KL, FL does not appear to affect the
differentiation, but rather the production, of DC.196
Production of DC from mobilized CD34+ peripheral blood
progenitor cells (PBPC) by GM-CSF and TNF- is enhanced by KL and FL
individually; combining them results in an additive
response.271
KL or FL (in combination with other cytokines) promotes DC formation
from uncommitted thymic precursors,272 but the identity and
responsiveness to KL or FL of committed lymphoid-derived CFU-DC remains
to be determined.
In vivo treatment of mice with FL results in a dramatic increase in the
number of myeloid- and lymphoid-derived functional DC in BM, spleen,
thymus, peripheral blood, gastrointestinal lymphoid tissues, and other
tissues, indicating an absolute increase in functionally mature DC
rather than a redistribution.273 In contrast, administration of KL, GM-CSF, or IL-4 to mice does not expand the
number of DC in the spleen. A key role of FL in DC generation is
further supported by reduced numbers of DC in FL-deficient mice.248
| |
LONG-TERM RECONSTITUTING MURINE STEM CELLS ARE HETEROGENEOUS WITH
REGARD TO c-kit AND Flt3 EXPRESSION |
Many studies have suggested that most, if not all, pluripotent
long-term reconstituting murine stem cells (LTRC; purified by various
methods from BM, fetal liver, and the intra-embryonic aorta-gonad-mesonephros) express
c-kit.184-188,274-276 Particularly noteworthy was a
study in which a single
LinSca-1+CD34low/-c-kit+
stem cell efficiently long-term reconstituted as much as one of five
transplanted mice.277 In addition, cells with the same phenotype isolated from primary recipients were able to reconstitute secondary recipients.277 The corresponding
c-kit population was not investigated. Although
these studies have clearly established that a large fraction and
probably most LTRC are c-kit+, they do not
necessarily rule out the possibility of a coexisting, and probably less
frequent c-kit LTRC, because the
reconstitution assays might not have been optimal for detecting the
LTRC activity of a (putative) c-kit stem
cell population.
In support of the potential existence of
c-kit stem cells,
c-kit murine BM cells without detectable
c-kit expression but with LTRC, but no short-term
reconstitution activity, have been identified.278 One study
identified a minor but efficient c-kit LTRC
population (0.005% of BM cells).279 The absence of
c-kit expression was verified at the cell surface as well as by
RT-PCR. As few as 10 of these cells efficiently generated all blood
cell lineages for the life span of the mice and showed extensive in vivo self-renewal ability, as assessed through serial transplantation. In contrast, as many as 1,000 of these cells showed no ability to
promote radioprotection.279 This is in contrast to most
c-kit+ LTRC (with the exception of
CD34/low c-kit+ stem
cells277), which in general have been found to also be enriched in short-term reconstituting and radioprotective
ability.184-186,188
The existence of an LTRC population with little or no c-kit
expression is also supported by another study280 in which
candidate stem cells were subfractionated into
c-kitlow and c-kit<low (no
detectable cell surface expression but positive for c-kit mRNA)
populations, representing 0.006% and 0.008% of the BM cells, respectively. These two populations did not differ in their capacity to
provide donor long-term multilineage reconstitution in primary irradiated recipients. However, when BM from primary recipients was
transplanted into secondary recipients, multilineage donor reconstitution could only be obtained from cells whose origin was
c-kit<low stem cells.280 Tertiary
recipients receiving cells derived from c-kit<low
stem cells were also efficiently reconstituted.280
Other investigators have subfractionated murine BM progenitor/stem
cells based on different levels of c-kit expression. In one
study, murine BM stem cells were isolated by counterflow centrifugal elutriation; subsequently fractionated into
c-kitneg, c-kitdull, and
c-kitbright subpopulations; and administered to
unirradiated W/Wv
recipients.187 One hundred c-kitbright
cells were sufficient to repopulate lympho-hematopoiesis in
W/Wv recipients, whereas as many as 2.5 × 104 c-kitdull or 5 × 105 c-kitneg cells had no LTRC
activity.
Whereas the majority of BM colony-forming cells in normal mice are
c-kitbright, most progenitors from 5-FU-treated
mice are c-kitdull.281 Cells resistant
to 5-FU represent predominantly dormant progenitor cells; moreover,
c-kitdull progenitor cells, unlike
c-kitbright progenitor cells, require multiple
cytokines to be recruited to proliferate and develop in culture into
c-kitbright progenitor cells. This suggests that
the most primitive murine progenitors might be
c-kitdull.281
The different conclusions reached in these studies might simply reflect
that LTRC are heterogeneous with regard to c-kit expression and
that differences in purification strategies and reconstitution assays
might result in enrichment and detection of different subpopulations of
stem cells. For instance, it is possible that the in vitro (cytokine
stimulation) and in vivo (5-FU treatment) manipulation of these cells
might modulate (up or down) the expression of c-kit. Thus,
although a certain level of c-kit expression might prove useful
for purification and characterization of LTRC by one specific procedure, it is not necessarily transferable to other methods.
Collectively, these studies suggest that, although most murine LTRC
express low or high levels of cell-surface c-kit, they coexist
with less frequent subpopulations of LTRC with undetectable c-kit expression. However, cells found to be
c-kit by flow cytometry are not necessarily
devoid of cell-surface c-kit expression, because the limit of
detection of this method is around 500 molecules per cell. In addition,
the finding of c-kit mRNA expression using the much more
sensitive RT-PCR method might be due to a minor contaminating
c-kit+cell population and does not necessarily
reflect cell-surface expression of c-kit. Thus, currently it
appears most correct to define apparently
c-kit stem cells as
c-kit<low.280 Because these
c-kit<low stem cells appear to represent highly
quiescent LTRC, they might exclusively promote late, rather than early,
engraftment and have a higher self-renewal capacity than most
c-kit+ stem cells, as shown through stringent
serial transplantation assays.279,280 The inability of
c-kit/c-kit<low murine
BM cells to provide long-term reconstitution in other studies might be
a direct consequence of such stem cells being present in low numbers
and/or not activated when transplanted after standardized
myeloablative or nonablative regimens.
In the stem and progenitor cell compartment in mice, the flt3 receptor
has been found in LinSca-1+AA4+
fetal liver cells,19,166
LinSca-1+ BM cells,19,166 and
WGA+15-1.1Rh123 bright and dull
cells.282
Virtually all AA4+CD34+ fetal liver cells
express c-kit. These, as well as
LinSca-1+c-kit+ BM
cells, contain distinct flt3+ and flt3
subpopulations, and the long-term repopulating activity appears to be
predominantly found in the flt3
subfraction.45 Thus, most murine LTRC appear to be
c-kit+ but
flt3/flt3<low. This observation, combined
with flt3+ stem cell populations having a lower fraction of
cells residing in G0 than flt3 stem cells,
has led to the proposal that flt3+ repopulating cells might
represent an activated subset of stem cells.45,187 However,
note that subpopulations of flt3+ stem cells are quiescent
and capable of promoting long-term reconstitution.45 Additional long-term serial transplant reconstitution studies using
flt3 and flt3+ stem cell populations could
provide more definite information regarding the self-renewal capacity
of flt3 and flt3+ stem cell populations.
| |
IN VITRO GROWTH-PROMOTING ACTIVITIES OF KL AND FL ON CANDIDATE
MURINE STEM CELLS AND PRIMITIVE MYELOID PROGENITOR CELLS:
POTENT SYNERGISTIC FACTORS |
A characteristic of the most primitive hematopoietic progenitor/stem
cells is the requirement for simultaneous activation through multiple
cytokine receptors to allow recruitment into active cell
cycling.2,4
Based on different patterns of growth-promoting activities on candidate
stem cells and their ability to synergistically interact with other
factors, cytokines can be grouped into different classes (Table 4). Synergy appears to be most
pronounced when cytokines from different classes are
combined.2 KL and FL are the only identified members of a
distinct group of early acting stem cell factors with unique and potent
activities on a variety of candidate murine stem cell populations.
Although they have little or no in vitro growth-promoting
activity when acting alone, both
KL162,197,222,223,281,283-292 and
FL45,48,49,166,205,206,223,245,293 can act in combination
with most, if not all, other cytokines from the two groups of early
acting cytokines to enhance growth of primitive murine progenitor/stem
cells through enhanced recruitment of otherwise quiescent progenitor
cells and enhanced proliferative activity.
Several studies involving single-cell cloning and delayed addition of
cytokines have shown that the effects of KL and FL are mediated
directly on the primitive progenitor cells, ruling out indirect effects
mediated by other cells. However, the extent of synergy exhibited by KL
and FL, both with regard to recruitment and enhanced proliferation,
varies considerably, depending in part on the interacting cytokine(s)
and the specific target population investigated. Although the magnitude
of synergy a specific cytokine exhibits in combination with KL and FL
is likely to result from interactions of the distinct signaling
pathways involved, it might also be a reflection of the heterogeneity
in expression of other cytokine receptors on primary hematopoietic cell
populations.2,4 When directly compared and combined with
the same cytokine(s), KL often recruits a slightly higher number of
primitive murine myeloid progenitor/stem cells into in vitro
proliferation than FL
does.45,48,49,166,205,206,223,245,293-297 This occurs
independently of which cytokine is used as the synergistic factor. In
addition, the average size of the resulting colonies is usually
significantly larger in KL- than in FL-supplemented cultures. Finally,
the progeny of primitive murine progenitor cells usually remain more
undifferentiated in FL- than in KL-supported cultures.166,205,206,245
As already described in detail, the expression of flt3 appears more
confined to primitive progenitor cells than c-kit, which is
also highly expressed on various populations of more committed myeloid
progenitor cells (Fig 2). Thus, the smaller clone size and less
differentiated progeny observed in FL-supplemented cultures could
result from the loss of flt3 expression at an earlier stage than
c-kit. In addition, c-kit is expressed on a higher
percentage of primitive progenitor/stem cells than
flt3,45,166 which may explain the lower cloning frequency
of primitive murine progenitor cells cultured/supplemented with FL
rather than KL.
The activities of FL on primitive murine progenitor cells may overlap
and be redundant with those of KL, as suggested for a number of other
cytokines with activity on primitive hematopoietic progenitors.2,4 However, although KL and FL have largely overlapping activities, they can also synergize with each other to
promote in vitro growth of primitive murine progenitor/stem cells.205,206,245 This synergistic interaction might help
to explain why mice with a combined c-kit and flt3 deficiency
have a more severe stem cell defect than mice with a single deficiency in c-kit or flt3.227
| |
c-kit AND Flt3 EXPRESSION ON CANDIDATE HUMAN STEM CELLS |
Because no routine and optimal reconstitution assay exists for human
LTRC, its status with regard to c-kit and flt3 expression has
yet to be established. However, much has been learned from studies of
candidate human stem cells in various surrogate assays. c-kit
is highly expressed in the CD38 subfraction of
CD34+ BM cells,190,298 which, although
representing only 0.05% to 0.1% of MNC, contains most, if not all,
cells capable of long-term multilineage reconstitution of preimmune
fetal sheep and immune-deficient mice.299,300 c-kit
is also expressed on all cells in a population of purified quiescent
human stem cells that is devoid of progenitors responsive to defined
cytokines in vitro but highly enriched in long-term culture-initiating
cells (LTC-IC).301 Other studies have shown that most, if
not all, LTC-IC are c-kit+.189,191
In one study, CD34+c-kit cells
produced no colony-forming cells (CFC), although more CFC were formed
by CD34+c-kitlow than
CD34+c-kithigh cells after 9 weeks of
culture. In addition, c-kithigh cells emerged from
c-kitlow cells after 4 weeks of
culture.302
Enrichment of primitive human progenitor cells in the
CD34+c-kitlow fraction as compared with
the CD34+c-kithigh fraction of BM cells
was recently confirmed in long-term engraftment studies in preimmune
fetal sheep.303 Although few animals were transplanted in
this study, the findings clearly support that CD34+ human
BM cells expressing low levels of c-kit are enriched in cells
with an ability to provide long-term multilineage reconstitution. In
contrast, cells with no or high c-kit expression have less long-term reconstituting ability.303
Subfractionation of CD34+ cord blood into
c-kit, c-kitlow, and
c-kithigh populations shows a pattern similar to BM
in that c-kitlow cells appear to contain more
quiescent and blast cell progenitors.304
There is no evidence yet for a population of
c-kit/c-kit<low
long-term repopulating human stem cells. However, such a stem cell population is likely to be present at a very low frequency, and current
in vivo (and in vitro) reconstitution assays for human cells may be
inadequate for detection of such a highly quiescent stem cell
population. Therefore, the status of c-kit expression on the
earliest human hematopoietic stem cells remains to be elucidated in
more detail.
One study has suggested that virtually all BM cells expressing high
levels of CD34 and low levels of c-kit are
flt3.57 Because the most primitive human
stem cells have been suggested to express low levels of c-kit
and high levels of CD34,302,303 this finding would suggest
that the earliest human stem cells might not express detectable levels
of flt3. However, in another recent study,176 most
c-kitlow cells as well as
CD34+CD38 cells were found to coexpress flt3
at low levels, and primitive cobblestone area-forming cells appeared to
be flt3+ as well as flt3. However, the flt3
status of human LTRC remains to be investigated.
Our current knowledge regarding c-kit and flt3 expression on
hematopoietic stem cells is summarized in Fig 2. Most long-term reconstituting stem cells identified to date in murine reconstitution assays express c-kit.184-188,274-276 The few
studies investigating flt3 expression on LTRC suggest that most are
flt3 and that these might be more primitive/quiescent
than flt3+ LTRC.45,187 However, further studies
will be required to dissect the expression of flt3 on the earliest stem
cells.
The existence of c-kit<low LTRC has been shown as
well278-280 and, depending on the long-term reconstitution
assay and stem cell population used, LTRC may predominantly express
high, low, or undetectable levels of
c-kit.187,278-281,303
It is unclear whether such distinct patterns of c-kit and flt3
expression might help identify subpopulations of LTRC within a
hematopoietic hierarchy, although available data indicate the existence
of such a hierarchy (Fig 2). The most primitive stem cell is likely to
be less frequently and more deeply quiescent than stem cells further
down in the hierarchy. These characteristics might make it difficult to
purify and subsequently activate this stem cell population in standard
reconstitution assays, in which more activated stem cells might have a
repopulating advantage. Thus, a minor population of
c-kit<low (potentially
c-kit) stem cells that efficiently and
exclusively provides long-term reconstitution and has a high
self-renewal potential278-280 is likely to represent a
highly quiescent stem cell population. The status of flt3 expression on
this stem cell population remains to be determined, but some studies
indicate that flt3 is predominantly expressed on activated stem
cells45,187; thus, the earliest stem cells might also be
flt3. Such c-kit<low/
flt3<low/ stem cells might, upon activation, give rise
to long-term repopulating stem cells expressing detectable but low
levels of cell-surface c-kit but not
flt3.187,281,303 We propose that this stem cell population
could next give rise to
c-kithighflt3<low stem
cells.187,281,302,303 There is also evidence for an
activated stem cell population with more restricted long-term
repopulating activity that expresses high levels of c-kit as
well as flt3.45
It is important to emphasize that this represents a proposed and
simplified stem cell hierarchy, exclusively based on expression of
c-kit and flt3 and predominantly based on studies in mice. In
addition, the information regarding flt3 expression on LTRC is much
more limited than for c-kit (in particular for human stem cells). Furthermore, heterogeneity would be expected within each level
of the hierarchy based on variable expression of other, potentially
important stem cell molecules. Thus, additional studies will be
required to confirm or redefine the proposed stem cell hierarchy.
| |
IN VITRO GROWTH PROMOTING ACTIVITIES OF KL AND FL ON PRIMITIVE
HUMAN HEMATOPOIETIC PROGENITOR/STEM CELLS |
A similar pattern of growth-promoting activities of
KL172,191,199,200,224,226,254,302,304-310 and
FL48-50,192,207,208,224,293,311,312 is observed on
primitive human hematopoietic progenitor cells, as described above for
murine progenitors. When stimulated by KL or FL alone, primitive human
progenitor cells isolated from fetal liver, cord blood, or BM show
little or no growth response, but both ligands in combination with
other early acting cytokines synergistically enhance growth in a direct
manner. Whereas multiple studies on different populations of primitive
murine progenitor cells have found KL more efficient than FL at
recruiting primitive progenitor cells into proliferation, several
studies on enriched primitive human progenitor cells indicate that FL
is at least as efficient as KL at recruiting human
cells.192,207,313-315 FL also appears to be more efficient
than KL at maintaining primitive human progenitor cells in a less
differentiated state.313-316 Again, this might result from
the more restricted expression of flt3 on more committed progenitor
cells.
| |
ROLE OF c-kit/KL AND Flt3/FL INTERACTIONS IN MAINTAINING
STROMA-DEPENDENT LONG-TERM HEMATOPOIESIS IN VITRO |
In the mouse, LTRC can be quantified by a competitive repopulation
assay; an equivalent assay for human stem cells does not currently
exist. Accordingly, the ability of candidate human stem cells to
produce committed progenitors over extended periods of culture (minimum
of 5 weeks) on established stromal cell layers has been used as a
surrogate human stem cell assay, although this should not be considered
to represent a true stem cell assay.313,314,317,318
Murine LTC-IC express c-kit and, although their optimal growth
and differentiation in stroma-dependent cultures is enhanced by KL,
their formation and maintenance appear to be
KL-independent.275,319,320 Furthermore, no difference in KL
expression is observed between cell clones capable and incapable of
maintaining long-term repopulating cells, and the addition of exogenous
KL does not reverse the inability of certain clones to support
long-term hematopoiesis.320 Similarly, the ability of
several stromal cell lines to conserve long-term marrow repopulating
stem cells is unaffected by c-kit blocking antibodies, whereas
their ability to promote myelopoiesis is virtually eliminated by the
same antibody.275,320 Finally, LTC-IC numbers are only
marginally reduced in W mutant mice.319
Human LTC-IC, like those of mice, express c-kit but do not
depend on c-kit activation for survival; but the addition of
c-kit blocking antibodies to long-term cultures inhibits
production of mature myeloid and erythroid progenitor cells from human
stem cells.189,302,321,322 Although Sl/Sl
fibroblasts are as efficient as normal murine fibroblasts or irradiated
human marrow feeder layers at supporting maintenance and clonogenic
cell output of LTC-IC, KL in the absence of feeder layers can also
efficiently maintain LTC-IC.322 This suggests that KL,
although not required, can support these primitive cells. The superior
ability of BM stromal cells to promote long-term hematopoiesis compared
with umbilical cord vein endothelial cells or human fibroblasts does not appear to be mediated through c-kit, because these stromal cells do not differ in their expression of soluble or membrane-bound KL.323
Although less is known about the expression and function of flt3 on
LTC-IC, several lines of data suggest that LTC-IC (at least in part)
express flt3 and that FL, like KL, can enhance their growth and
differentiation.17,313,314 Antisense oligonucleotides against flt3 almost completely block the ability of human LTC-IC to
form mature myeloid progenitor cells in BM stromal
cultures.17 Furthermore, FL on its own has the unique
ability to expand human LTC-IC which are reduced in cultures containing
KL alone314 and in combination with TPO it maintains LTC-IC
over prolonged culture.229
| |
KL PROMOTES ADHESION OF HEMATOPOIETIC PROGENITOR CELLS AND MAY
FUNCTION IN ITS MEMBRANE-BOUND FORM AS A HOMING RECEPTOR FOR
c-kit+ CELLS |
A critical role in hematopoiesis has been implicated for the
very late antigen (VLA) family of integrins.324-328 KL is a
potent stimulator of the adhesion of mast cells, hematopoietic
progenitor cell lines, and CD34+ BM progenitor cells to
fibronectin and vascular cell adhesion molecule-1 (VCAM-1) through
activation of VLA-4 and VLA-5.329-332 Only one hundredth of
the amount of KL is required to induce adhesion compared with the
amount needed to induce proliferation.331
The ability of KL to promote adhesion may have physiologic and
potential clinical significance, because adhesion molecules are thought
(1) to be important regulators of anchoring, migration, and
mobilization of stem cells; (2) to affect cell growth and differentiation; and (3) to improve gene transfer into candidate hematopoietic stem cells.333-335
Membrane-bound KL is likely to function in part as an adhesion molecule
for mast cells and hematopoietic progenitor cells.336-340 The ability of KL to promote adhesion of c-kit+
hematopoietic progenitors might explain why progenitor cells exposed to
blocking c-kit antibodies show reduced homing
efficiency.341 The effect of KL on homing and migration
might also result from its chemotactic effect on mast cells and
hematopoietic progenitor cells.342-344 Studies have not yet
been performed to determine whether FL has a similar ability as KL to
promote adhesion of hematopoietic cells.
| |
KL AND FL PROMOTE VIABILITY OF PRIMITIVE HEMATOPOIETIC
PROGENITOR/STEM CELLS |
Although the primary function of KL and FL in early hematopoiesis might
be to induce the growth of quiescent progenitor/stem cells through
synergistic interactions with other early acting cytokines, there is
also ample evidence that KL345-350 and
FL,166,311,351,352 in the absence of other cytokines,
selectively promote viability rather than proliferation of primitive
murine and human progenitor cells, including the LTRC in the case of KL.345,347,348
| |
INHIBITORS OF KL AND FL ACTIVITY ON PRIMITIVE HEMATOPOIETIC
PROGENITOR CELLS |
Although the physiologic significance of growth inhibitory cytokines in
steady-state hematopoiesis remains to be established, the interactions
of transforming growth factor- (TGF-) and tumor necrosis
factor- (TNF-) with KL and FL on primitive hematopoietic progenitor cells are worth mentioning. TGF-, a potent inhibitor of
primitive hematopoietic progenitor cell growth,353 hinders the viability and growth-stimulatory effects of KL and FL on primitive murine and human hematopoietic progenitor
cells.224,295,351,354-356 TNF-, a cytokine that can
directly stimulate or inhibit the growth of primitive and committed
hematopoietic progenitor cells,357 inhibits KL- and
FL-stimulated growth, viability, and expansion of normal primitive
murine and human progenitor cells.296,314,358-360
| |
DISTINCT HEMATOPOIETIC ACTIVITIES OF MEMBRANE-BOUND KL |
As described above, KL and FL are produced in membrane-bound as well as
in soluble forms. In addition to potentially functioning as adhesion
molecules by binding to their respective receptors, membrane-bound KL
has activities distinct from those of soluble KL.
Sl/Sld mutant mice that only produce the
secreted form of KL have the same hematopoietic defects characteristic
of Sl/Sl mutant mice, suggesting that there is an essential
role for membrane-bound KL.88,92 When cDNAs encoding
soluble or membrane-bound isoforms of human KL are transfected into
stromal cells derived from Sl/Sl mice, membrane-bound KL
maintains human hematopoiesis longer than secreted KL.89
Membrane-bound KL (or immobilized anti-kit antibodies), when
compared with soluble KL, induces (1) more c-kit kinase
activity, (2) less rapid downregulation of cell surface c-kit
expression, and (3) enhanced stability of
c-kit.361,362 Thus, the difference in activity
between soluble and membrane-bound KL might result from the soluble
c-kit/KL complex being rapidly internalized and degraded,
resulting in transient tyrosine kinase activation of c-kit. In
contrast, if the membrane-bound c-kit/KL complex is not
internalized and degraded, it could result in a sustained period of
enhanced c-kit kinase activity.
| |
HEMATOLOGIC EFFECTS OF KL AND FL IN VIVO |
Mutations in the W or Sl loci result in reductions
of various primitive hematopoietic progenitor cells,10 but
except for erythrocytes, the numbers of other mature blood cells appear
normal under steady state conditions. Sl/Sld mice,
although severely anemic, survive to adulthood; administration of KL
improves their anemia, which reappears when KL treatment is
discontinued.36 KL treatment also increases their
platelets, granulocytes, monocytes, and lymphocytes above the levels
seen in wild-type mice36 and increases CFU-S numbers in
their BM and spleen.345
Sl/Sld mice display a dysfunctional regulation of
platelet production in response to cytotoxin-induced thrombocytopenia;
they do not undergo the rebound thrombocytosis observed in wild-type mice after 5-FU treatment.167 However,
Sl/Sld mice treated with 5-FU have a rebound
thrombocytotic response after the administration of KL.167
Enhanced KL mRNA expression in response to 5-FU-induced
thrombocytopenia in the BM of normal mice and c-kit expression
on immature megakaryocytes further substantiate the role KL plays in
promoting platelet recovery after BM suppression.167 KL
also increases the number of megakaryocytes and platelets in normal
mice.167
The role of KL in promoting platelet production after hematopoietic
injury might be due to its ability to synergize with TPO to enhance
megakaryocyte progenitor cell growth.217 Although TPO is
the primary regulator of megakaryocytopoiesis and platelet production,217,363 mice deficient in TPO or c-mpl
(the TPO receptor) expression do produce functionally mature platelets,
albeit at dramatically reduced levels.363 In addition, KL
administration to TPO-deficient mice increases platelet
counts.364 Thus, it appears that there are TPO-independent
mechanisms for platelet production in which KL might also play a role.
Sl/Sl mice lacking functional KL die at day 15 or 16 of
gestation.29 However, the total number of fetal liver cells
in normal or Sl/Sl mice increase by more than 10-fold
between day 13 and 15 of gestation and, although the fetal liver
cellularity in the KL-deficient mice is only 20% to 25% of wild-type
fetal liver, the increase in fetal liver cells is
similar.186 More importantly, the number of cells with a
stem cell phenotype
(LinSca-1+Thy-1lo) and CFU-S
activity also increases in Sl/Sl mice from day 13 to
15.186 This suggests that KL might not be essential for
early hematopoietic development in mouse embryos and that fetal
hematopoietic progenitor/stem cells can expand/self-renew in the
absence of KL.
In mice with viable W mutations, disruption of hematopoiesis
appears largely restricted to erythropoiesis and mast cell generation. Specifically, in BM of W41/W41
mice (with a partial c-kit signaling deficiency), the number of
erythroid, myeloid, pre-B, and multipotent progenitor cells, as well as
LinSca-1+ candidate stem cells and LTC-IC,
are at near-normal levels.319 However, long-term
repopulating units in W41/W41
BM are reduced 17-fold.319 Furthermore,
W41/W41 fetal liver cells are
qualitatively and quantitatively close to normal in their short-term
reconstituting ability but promote less long-term
reconstitution.365 W42 mutant fetal
liver cells (completely silent c-kit receptor) show an even
more pronounced inability to provide long-term reconstitution. Thus,
although c-kit/KL interaction might not be critical for stem
cell generation and expansion during early ontogeny, their sustained
self-renewal might in fact be KL-dependent. An important role for KL in
promoting reconstitution by LTRC is also supported by enhanced
expression of KL following myeloablative treatment167,366 and the ability of endogenous and exogenous KL to promote survival and
hematopoietic reconstitution of mice and dogs after
myeloablation.366-370
Other findings indicate that KL plays an important role in steady-state
adult hematopoiesis. As early as 2 days after injection of normal mice
with c-kit antibodies, most myeloid and erythroid cells
disappear, although the BM cellularity remains normal.183 The content of in vitro clonogenic myeloid progenitor cells and CFU-S
in the BM declines rapidly, whereas a concomitant increase in B-cell
precursors is observed.183
KL administration in vivo to normal mice results in an increase in
peripheral white blood cells (WBC), predominantly neutrophilic granulocytes, and also a slight increase in lymphocytes.371
BM cellularity is not affected, and its content of in vitro clonogenic myeloid progenitor cells and day-8 CFU-S is only slightly
enhanced.371 In contrast, the number of myeloid progenitors
and CFU-S in the spleen increases dramatically, and KL induces a more
rapid and pronounced leukocytosis in splenectomized
mice.371
KL administration to mice for 7 days results in depletion of candidate
BM stem cells (LinSca-1+Thylo)
and a corresponding reduction in radioprotective
ability.372 A concomitant increase in both these
hematopoietic parameters, as well as multilineage long-term
reconstituting activity, is observed in spleen and peripheral
blood.372 Because the total number of
LinSca-1+Thylo did not
significantly change, it was postulated that administration of KL does
not result in a net expansion of long-term reconstituting stem cells,
but rather redistributes existing stem cell activity to peripheral
sites.
The progenitor/stem cell mobilizing ability of KL has been investigated
extensively in various animal models. Low doses (25 µg/kg/d) of KL
have little or no effect on the number of PBPC in splenectomized mice,
but KL synergistically enhances WBC counts and mobilization of PBPC in
combination with an optimal dose of G-CSF (200 µg/kg/d).373 The increase includes cells with both short-term and long-term repopulating activity.374
Administration of KL to normal mice results in a threefold increase in
LTRC that are predominantly redistributed to peripheral blood and the
spleen.375 KL in combination with G-CSF also mobilizes
progenitor/stem cells to the blood that are capable of
engrafting lethally irradiated dogs and
baboons.376-379 Although the ability of KL plus
G-CSF-mobilized progenitor cells to long-term engraft baboons and dogs
remains to be established, it appears that blood count recovery occurs earlier with grafts mobilized with KL plus G-CSF than with G-CSF alone.376-378
In humans, daily administration of KL at dosages of up to 50 µg/kg
for 14 days does not increase the number of peripheral blood
CD34+ cells, but does increase the absolute number of
CD34+ cells and assayable primitive and committed myeloid
progenitor cells in BM.380 In a phase I/II study in
patients with high-risk breast cancer, mobilization of progenitor cells
to peripheral blood by KL plus G-CSF was superior to G-CSF
alone.381
The administration of KL plus G-CSF in mice has shown interesting
kinetic aspects of distribution/expansion of stem cells.382 The most dramatic increase in repopulating ability of peripheral blood
stem cells is observed immediately after cytokine treatment, concomitant with a reduction in reconstituting ability of the BM.
Subsequently, the repopulating activity of peripheral blood stem cells
declines to normal levels within 6 weeks of termination of cytokine
treatment, whereas the repopulating activity of BM cells increases by
day 14 to levels 10-fold higher than BM cells from untreated mice. The
mechanism for this large yet temporary increase in the repopulating
activity of BM stem cells after administration of KL and G-CSF is
unclear. Increased numbers of primitive
(CD34+CD38) cells are also seen in the BM of
rhesus monkeys as long as 2 to 3 weeks after administration of KL and
G-CSF.383
In vivo daily administration of recombinant human FL (500 µg/kg/d) to
normal mice stimulates an increase in WBC.384 The increase in WBC counts is reflected in an increase in the number of lymphocytes, granulocytes, and especially monocytes.384 A small decrease
in hematocrit after 10 days of treatment is reversed upon cessation of
treatment. BM cellularity is not affected by FL treatment. The number
of CD4+ and CD8+ T cells in the BM is reduced,
as are mature (B220+IgM+) B
cells.384 In contrast, FL treatment increases the number of
immature (B220+IgM) B cells. The number of
monocytes and granulocytes increases as well, as do DC, whereas the
number of immature erythroid cells is reduced by 90%.384
This decrease may result from the mobilization of erythroid precursors
from BM and/or an altered differentiation pathway for
progenitors of these erythroid precursors; the exact cause is not
known.
Splenic cellularity increases after 10 days of FL treatment, with
little effect on CD4+ and CD8+ T cells, but
with an increase in NK cells and DC. Most striking is the ninefold
increase in B220+IgM B-cell progenitors,
with only a marginal effect on splenic mature B220+IgM+ B cells. As in BM, the number of
splenic myeloid cells increases as much as 10-fold. Splenic primitive
erythroid cells also increase, although these cells decrease in
BM.384
The number of BM GM progenitor cells increases fivefold after 3 days of
FL treatment. The number of these cells subsequently decline during the
next 12 days of treatment, and decrease to 50% below control levels 1 week after cessation of FL treatment.384 BFU-E numbers in
BM increase slightly after 3 days of FL treatment, but decrease
subsequently. Colony-forming unit granulocyte, erythrocyte, monocyte,
megakaryocyte (CFU-GEMM) numbers also peak early in BM
and subsequently return to control values. CFU-GM, BFU-E, and CFU-GEMM
increase 123-fold, ninefold, and 108-fold, respectively, in spleen.
Maximum levels are seen after 8 to 10 days of treatment, and these
numbers return to control levels 1 week after treatment. In peripheral
blood, a 537-fold, 113-fold, and 585-fold increase in CFU-GM, BFU-E,
and CFU-GEMM, respectively, is observed after 10 days of FL
treatment.384 FL also mobilizes primitive, day-13 CFU-S
into peripheral blood. Finally, an increase in cells with a stem cell
phenotype
(LinSca-1+kit+) is
observed in the BM, spleen, and peripheral blood of FL-treated mice.384
Cells mobilized to peripheral blood with FL have been shown to have
long-term (6 months) reconstituting ability.385 FL also mobilizes progenitor/stem cells into the peripheral blood of nonhuman primates and shows synergy with either G-CSF or GM-CSF with regard to
mobilizing ability.385,386
Preliminary results from human clinical trials show that the
administration of FL to normal, healthy volunteers is safe and effectively elevates the numbers of CD34+ cells and DC in
peripheral blood (Mel Lebsack and Eugene Maraskovsky, Immunex; personal
communication). The in vivo hematologic/hematopoietic effects of FL and KL are summarized in
Table 5.
| |
TARGETED DISRUPTION OF THE Flt3 RECEPTOR AND FL GENES |
Whether flt3 or FL are required for normal hematopoiesis has been
addressed by creating mice that carry a homozygous deletion of most of
the gene encoding the flt3 receptor227 or
FL.248 Mice in which either the flt3 receptor or ligand
have been knocked out are generally healthy, which is in marked
contrast to the lethality observed in mice homozygous for the deletion
of the gene encoding the c-kit receptor or KL
protein.24 The flt3 knockout mice have normal levels of
peripheral blood cells.227 However, the loss of a
functional flt3 receptor results in a reduced number of early B-cell
precursors and a defect in primitive stem cells, as measured in a
long-term competitive repopulation assay. Upon adoptive transfer to
irradiated secondary recipients, stem cells from flt3
deficient/ mice have an impaired ability to
repopulate myeloid, T-, and B-lymphoid lineages.
Mice bearing targeted disruptions in the flt3 receptor were bred with
mice carrying mutations in the c-kit receptor to generate animals of the genotype flt3/flt3
W/Wv. Offspring had severely reduced numbers of
hematopoietic cells and died between 20 and 50 days of
age.227 These experiments demonstrated a requirement for
both flt3 and c-kit receptors in the development of a normal,
functional hematopoietic system.
There is no evidence that FL binds to any other protein in addition to
the flt3 receptor. Similarly, no other ligands are known that bind to
the flt3 receptor. Thus, one would predict that mice homozygous for a
targeted disruption of the FL gene would have an identical phenotype to
flt3 receptor knockout mice. FL knockout mice, like the flt3 receptor
knockout mice, have a normal, healthy appearance.248 They
have a defect in early B-cell development, as do the flt3 receptor
knockout mice. However, a couple of significant observations have been
made in analyzing the FL knockout mice that were not reported with the
flt3 receptor knockout mice. There is a significant reduction in the
cellularity in the peripheral blood, spleen, and BM of FL knockout
mice, whereas no change in cellularity was reported in the flt3
receptor knockout mice. DC in the spleens of these animals are also
significantly reduced. Most notable is a lack of NK cell activity in
the spleens of mice treated with either poly IC or IL-15. It is unclear
if these unique observations in the FL knockout mice reflect a truly different phenotype or whether strain variations or the depth of
analysis account for the observed differences.
| |
HUMAN SERUM/PLASMA LEVELS OF KL AND FL |
Levels of KL in human serum from normal individuals are usually found
in the range of 2 to 5 ng/mL.387 KL serum levels have also
been examined in a wide variety of patients with hematopoietic disorders, and they do not vary much or appear to be of clinical significance.388
In contrast to the relatively high levels seen with KL, serum levels of
FL in normal individuals average less than 100 pg/mL, which is the
limit of detection of the enzyme-linked immunosorbent assay.389 FL levels are not elevated in a
variety of anemias that predominantly affect only the erythroid
lineage389 or in patients with rheumatoid arthritis,
systemic lupus erythematosus, AML, ALL, or human immunodeficiency virus
(Lyman et al, unpublished observations).
In contrast, serum levels of FL are highly elevated in patients with
hematopoietic disorders that specifically affect the stem cell
compartment. Thus, a majority of patients with anemias affecting
multiple hematopoietic lineages (eg, Fanconi anemia, acquired aplastic
anemia) have highly elevated levels of FL (up to 10 ng/mL).389 Cancer patients treated with chemotherapy
and/or radiation also have highly elevated levels of
FL.390
The simplest interpretation of these data is that the loss of
functional stem/progenitor cells leads to the loss of a negative regulator of FL production made by the stem/progenitor cells. FL
concentrations in blood then become elevated (to a physiologically relevant level) as part of a compensatory hematopoietic response to
drive the proliferation of the remaining stem/progenitor cells.
Serum levels of FL returned to normal in a Fanconi anemia patient after
a cord blood transplant that cured the pancytopenia.389 Similarly, successful treatment of acquired aplastic anemia patients with either BM transplants or immunosuppressive therapy also led to a
return to normal of FL serum levels.390 These data suggest that restoration of stem cells in these patients is associated with a
return of FL serum levels to those measured in normal, healthy
individuals and that FL serum levels may be a surrogate marker for stem
cell activity or content in BM.
However, the hypothesis cited above does not explain why about 50% of
patients with refractory anemia (RA) have elevated levels of
FL,391 because RA is not considered a disease of either
stem cell number or activity. FL serum levels are not elevated in any of the other FAB subclasses of myelodysplasia,391 and the
reason only some RA patients have elevated serum levels is unknown.
| |
POTENTIAL CLINICAL USES OF KL AND FL |
Because both KL and FL have potent effects on primitive hematopoietic
cells, the majority of clinical uses envisioned are designed to exploit
this activity (Table 6). Both proteins
synergize with a wide range of cytokines, and it is possible that they
could enhance the effects of other cytokines that function on primitive as well as more differentiated hematopoietic cells.
Adverse events associated with KL administration in humans in phase I
and phase II trials have been primarily dermatologic reactions (eg,
pruitic wheals with erythema at the site of injection) and, more
rarely, multisymptom systemic anaphalactoid
reactions.8,179,181,182 The most likely cause of these
effects is mast cell hyperplasia, activation, and mediator release; as
a result, prophylactic antihistamine treatment has been incorporated
into clinical protocols.8
Limited data on the hematologic effects of FL in humans have been
reported392 and indicate that FL appears to have a good safety profile. This is consistent with the observation that no overt
toxicities were seen when short courses of FL were administered to
animals in vivo.384,386,393
Stem cell mobilization.
As described above, KL and FL may prove useful for mobilizing or
expanding BM stem cells in vivo. These stem cells can be used in
various transplantation settings, in particular autologous and
allogeneic stem cell transplantation of cancer patients after high-dose
chemotherapy. In addition, mobilized stem cells might be excellent
targets for gene therapy383,394-397 (see below). The use of
KL and/or FL along with a second cytokine, such as G-CSF or
GM-CSF, appears to increase the number of stem cells mobilized (see
above). Stem cells mobilized/expanded in vivo by KL plus G-CSF might be
better targets for gene therapy than those mobilized with G-CSF
alone.366,374,382,383,394 However, qualitative differences in stem cell populations mobilized by different cytokine treatments have not yet been examined in sufficient detail and therefore require
further study.
Ex vivo stem/progenitor cell expansion.
Ex vivo expansion of hematopoietic progenitor/stem cells is an area of
intense study due to its clinical potential. However, a number of
obstacles must be overcome before it can be established whether or not
ex vivo-expanded progenitor/stem cells represent an improved
therapeutic modality in various settings (for detailed reviews see
Williams,398 Lange et al,399 and
Emerson400).
Ex vivo-expanded progenitor/stem cells could reduce the need for
extensive BM harvests or leukaphereses and enable repetitive cycles of
high-dose chemotherapy. Because contaminating tumor cells in autologous
stem/progenitor cell grafts can contribute to
relapse,401,402 selective ex vivo expansion of
progenitor/stem cells may also reduce or eliminate such tumor
cells.399,400
Murine in vitro clonogenic progenitor cells as well as CFU-S
efficiently expand when stimulated by KL or FL in combination with
cytokines such as IL-1, IL-3, IL-6, IL-11, TPO, and
G-CSF.205,206,222,287,345,403 Importantly, KL in
combination with IL-1, IL-6, or IL-11 promotes efficient expansion of
murine (short-term repopulating) progenitor cells without loss of
long-term reconstituting ability in the expanded
graft.403-406
Because IL-3 has been used extensively in ex vivo expansion protocols,
it is noteworthy that IL-3 appears to compromise the long-term
reconstituting ability of murine grafts expanded in either KL or FL in
combination with other early acting cytokines.404,407
Optimal expansion of human progenitor cells requires the interaction of
KL with multiple cytokines, including IL-1, IL-3, IL-6, GM-CSF, G-CSF,
and EPO.306-308,408-410 As discussed above, the membrane-bound form of KL is more efficient than the soluble form at
maintaining progenitor cell production in stromal cell
cultures,89 indicating that membrane-bound KL might be
beneficial for maintaining primitive progenitor/stem cells. FL also
expands human myeloid progenitor cells in combination with other
cytokines.192,208,224,297,311,313,315,316,411
Although KL and FL are efficient at stimulating production of
multipotent and lineage-restricted myeloid progenitor cells from
candidate human stem cells, the key question of whether ex vivo
expansion protocols for human progenitor/stem cells maintain sufficient
pluripotent long-term repopulating stem cells remains unanswered.
Currently in patients receiving high-dose chemotherapy, the predominant
function of progenitor/stem cell grafts might be to provide efficient
short-term reconstitution, whereas long-term reconstitution might be
provided equally well by endogenous stem cells surviving the high-dose
treatment. However, if high-dose chemotherapy is further intensified,
it might become crucial to ensure that transplants also contain
sufficient LTRC.398-400 In the case of gene therapy, in
which the ultimate goal is the introduction of therapeutic genes into
LTRC, it is already paramount that such grafts contain
LTRC412 (see below). Thus, it will be important to
investigate the effects in ex vivo-expansion cultures on the earliest
human stem cells using techniques such as gene marking.413
Although not conclusive with regard to LTRC, some recent studies cast
light on the ability of FL and KL to maintain/expand candidate human
stem cells. In one study, FL alone had the unique ability to slightly
expand the number of primitive LTC-IC in
CD34+CD38 BM cells, whereas LTC-IC were
depleted in cultures containing KL alone.314 Furthermore,
in a detailed study of 16 different cytokines, a combination of FL, KL,
and IL-3 was both necessary and sufficient to obtain a 30-fold
expansion of 6-week LTC-IC.314 In other studies, FL and KL
were found to be equally efficient at stimulating the production of
progenitor cells for 30 days from CD34+CD38
progenitor cells cultured on stroma,313 whereas progenitor
cell output beyond 56 days was significantly higher in FL- than in KL-supplemented cultures.313 In addition, human
CD34+ BM cells expanded under stroma-free conditions in KL
plus IL-3 plus IL-6 in the presence (but not in the absence) of FL
provided long-term reconstitution of immune-deficient
mice.316 Other groups have found FL more efficient than KL
at expanding human LTC-IC.414 Another promising combination
of factors for the ex vivo expansion of stem/progenitor cells from cord
blood was the combination of FL and TPO, which allowed continuous
expansion of these cells for as much as 5 months.229
Gene therapy.
Hematopoietic stem cells are considered optimal targets for gene
therapy, because they display extensive capacity to self-renew and to
produce large numbers of progeny that are widely distributed throughout
the body. In addition, stem cells can be readily obtained from BM,
mobilized peripheral blood, or cord blood and can therefore be easily
manipulated in vitro.412,415,416
Gene transfer into mouse long-term repopulating stem cells can be
performed with high efficiency and success.417-421 In
contrast, gene transfer into stem cells in larger animal models
(including studies in humans) has been
disappointing.412,415,416
Currently, mouse retroviruses are the only vectors shown to integrate
permanently into host DNA, and most gene therapy protocols targeting
stem cells use these vectors. One of the caveats with such retroviruses
is that they cannot efficiently transduce and integrate into quiescent
cells.412,415,416 Therefore, stem cells that normally are
highly quiescent must be recruited into active cell cycle to enable
successful transduction with such vectors, and FL and KL may be of use
through their ability to efficiently trigger cell cycling of candidate
stem cells. In addition, it is possible that these early acting
cytokines might have a more beneficial effect on preserving the
self-renewal, pluripotentiality, and engrafting potential of targeted
stem cells than later-acting cytokines.
KL in combination with IL-3 and IL-6 efficiently promotes transduction
of mouse stem cells while maintaining their long-term reconstituting
ability.419,421 KL plus IL-3 plus IL-6 is also the
combination predominantly used to achieve retroviral transduction of
human hematopoietic progenitor cells, resulting in high gene transfer
efficiency to committed as well as more primitive human progenitor
cells (LTC-IC).422-426
Recent studies suggest that FL might be more efficient than KL at
promoting gene transfer into human hematopoietic progenitor cells.
Specifically, when combined with IL-3, FL is superior to KL at
promoting retroviral gene transfer to committed myeloid progenitor
cells, and the addition of KL (and other cytokines) to FL plus IL-3
significantly reduces the gene transfer efficiency.315 In
the absence of stroma or fibronectin, the combination of IL-3, IL-6,
and KL is unable to preserve the capacity of retrovirally transduced
human BM CD34+ progenitor cells to sustain long-term
hematopoiesis in immune-deficient mice in vivo.316 However,
when FL is added to this cytokine combination, the transfected cells
support long-term reconstitution of immunodeficient mice,316 although FL cannot fully replace the effect of
stromal cells.316 The ability of FL to preserve the
capacity of putative human stem cells to sustain long-term
hematopoiesis in immune-deficient mice does not necessarily imply that
FL enhances gene transfer to long-term repopulating stem cells. It is
also possible that FL might have a positive effect on the self-renewal
and/or engrafting potential of these cells.
KL and FL might also be used to enhance gene transfer into
hematopoietic stem cells through their ability to mobilize stem cells
to peripheral sites (described in detail above). Long-term reconstituting mouse stem cells mobilized to peripheral sites in
response to administration of KL alone can be as efficiently transduced
with retroviral vectors as mice treated with 5-FU.375 In
mice treated with a combination of G-CSF and KL, mobilized long-term
repopulating stem cells are expanded and transduced 2 to 3 times as
efficiently as BM from 5-FU-treated mice, making such cells
particularly attractive for gene therapy applications.394
The number of LTRC in the BM of mice and rhesus monkeys is expanded and
shows improved gene transfer 1 to 2 weeks after treatment with KL and
G-CSF.383 Similar studies of the efficiency of retroviral gene transfer to stem cells mobilized by FL in combination with G-CSF
in primates also show an increased efficiency of gene transfer (Harry
Malech, NIH, Bethesda, MD; personal
communication).
Efficient gene transfer of human c-kit+
hematopoietic cell lines has been achieved through targeting of
c-kit with a molecular conjugate vector coupled to
KL.427 However, whether a similar approach will be
successful in normal hematopoietic progenitor/stem cells and whether
permanent gene expression can be achieved remains unanswered.
Although these studies imply a role for KL and/or FL in human
gene therapy in hematopoietic stem cells, most of these findings have
been made in vitro or in immune-deficient mice and do not necessarily
reflect true human stem cells. Thus, reproduction of such findings in
nonhuman primates and eventually humans is essential.
Immunotherapy.
Immune DC, which may be thought of as professional antigen-presenting
cells, have been proposed as cellular vectors for either antitumor or
infectious disease vaccines, or as inducers of transplantation tolerance.428-430 The feasibility of using DC as
immunotherapy vectors in the clinic has been limited by the small
number of DC that can be isolated from the peripheral blood of normal
individuals.
Although both KL193,194,431 and FL196,271
stimulate the production of DC in vitro (see above), to date only FL
has been shown to stimulate DC generation in vivo.273 These
DC appear to be both myeloid and lymphoid derived.273
Therefore, FL could possibly be used as a vaccine adjuvant: DC subsets
would be expanded in vivo by treating individuals with FL, and then
antigen-based vaccines would be injected. The goal would be to enhance
the magnitude and quality of the immune response generated without the
need for chemical adjuvants. Alternatively, larger numbers of
circulating DC from FL-treated individuals could be isolated via
apheresis for ex vivo manipulation (eg, vaccine or tolerogen exposure),
followed by reinfusion of these DC.
Finally, and perhaps most promising, FL may have antitumor effects in
vivo that are immune-system mediated. FL administration to mice has
been shown to inhibit the growth of a fibrosarcoma cell line in vivo in
a dose-dependent manner.432 Administration of FL to mice
injected with a breast cancer cell line leads to rejection of these
cells in syngeneic mice,433 as does ectopic expression of
FL by these breast cancer cells.434 FL may stimulate DC
production, which in turn presents tumor antigen(s) to T cells, leading
to rejection of the tumors. NK cells are also likely to have a role in
this process.
| |
CONCLUDING REMARKS |
KL and FL, acting through their respective tyrosine kinase receptors
c-kit and flt3, have pleiotropic and potent effects on hematopoiesis in vitro and in vivo. Based on studies of the expression and function of the two receptors, it is now evident that the hematologic actions of these two cytokines are predominantly restricted to the progenitor/stem cell compartment. One important exception is the
functional expression of c-kit, but not flt3, on mast cells, which helps explain the adverse events associated with KL
administration in humans. The physiologic importance (if any) of the
residual expression of c-kit and flt3 on other mature cell
types remains unknown.
In the (long-term reconstituting) stem cell compartment, c-kit
appears to be expressed on more stem cells than flt3, and, although not
yet conclusively documented, c-kit might be expressed on
earlier stem cells than flt3. Although recent data suggest that the
earliest stem cells might express no or very low levels of
c-kit and flt3, the status of c-kit and flt3 expression
and function on hematopoietic stem cells needs to be studied in more depth, particularly in the human system.
Most of the hematopoietic activities of KL and FL appear to require a
synergistic interaction with other early acting or lineage-selective cytokines. c-kit/KL might be critical for maintenance and
self-renewal of long-term reconstituting stem cells, particularly in
adult hematopoiesis. In addition, these two ligands appear to be
essential for optimal production of mature hematopoietic cells from
stem cells. Accordingly, stem cells deficient in c-kit or flt3
expression are defective in their ability to reconstitute hematopoiesis
in myeloablated animals.
Interestingly, FL appears more critical for generation of lymphoid
progeny than KL. In contrast, multiple lines of data suggest that KL
inhibits B-cell development in mice.
The finding that FL plays a less crucial role than KL in the regulation
of myelopoiesis and erythropoiesis is not surprising, because flt3 is
generally expressed on less myeloid progenitor cells and is not found
on erythroid progenitor cells. Thus, both KL and FL appear to have a
dual function in hematopoiesis in that they both have activity on stem
cells and appear to act as critical early regulators of
myelopoiesis/erythropoiesis and lymphopoiesis, respectively.
The activities of FL and KL are distinct, although in some instances
they may be complimentary to, synergistic with, or antagonistic to each
other. It will be important to further dissect the distinct biological
activities of the membrane-bound and soluble forms of KL and to
determine whether membrane-bound FL functions differently from soluble
FL. Whether these key hematopoietic regulators are involved in diseases
or potentially could be used therapeutically remains to be further
investigated. In that regard, combination therapy with other cytokines
will be of particular interest.
| |
FOOTNOTES |
Submitted June 6, 1997;
accepted October 9, 1997.
Address reprint requests to Stewart D. Lyman, PhD, Department of
Molecular Genetics, Immunex Corp, 51 University St, Seattle, WA 98101;
or Sten Eirik W. Jacobsen, MD, PhD, Stem Cell
Laboratory, Department of Internal Medicine, University Hospital of
Lund, S-221 85 Lund, Sweden.
| |
ACKNOWLEDGMENT |
The authors acknowledge the extensive and important contributions of
colleagues at Immunex, especially Hilary McKenna, Ken Brasel, and
Eugene Maraskovsky, and also Doug Williams, Bali Pulendran, Subhashini
Srinivasan, Claudia Jochheim, and Dave Lynch for thoughtful discussions
and reviewing the manuscript. We also thank members of the Stem Cell
Laboratory, University of Lund including Ole Johan Borge, Veslemøy
Ramsfjell, Cui Li, and Ole Peter Veiby for valuable input and reviewing
the manuscript. We thank Hal Broxmeyer, Hans Drexler, Stefan Karlsson,
Jonathan R. Keller, Makio Ogawa, Francis W. Ruscetti, and Alexandra
Wodnar-Filipowicz for their critical review of the manuscript. Finally,
we thank Anne Bannister and Christine Jones for expert editorial
assistance.
| |
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N. Buza-Vidas, M. Cheng, S. Duarte, H. Nozad Charoudeh, S. E. W. Jacobsen, and E. Sitnicka
FLT3 receptor and ligand are dispensable for maintenance and posttransplantation expansion of mouse hematopoietic stem cells
Blood,
April 9, 2009;
113(15):
3453 - 3460.
[Abstract]
[Full Text]
[PDF]
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M. Cheng, H. N. Charoudeh, P. Brodin, Y. Tang, T. Lakshmikanth, P. Hoglund, S. E. W. Jacobsen, and E. Sitnicka
Distinct and Overlapping Patterns of Cytokine Regulation of Thymic and Bone Marrow-Derived NK Cell Development
J. Immunol.,
February 1, 2009;
182(3):
1460 - 1468.
[Abstract]
[Full Text]
[PDF]
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K. R. Mott, D. UnderHill, S. L. Wechsler, and H. Ghiasi
Lymphoid-Related CD11c+ CD8{alpha}+ Dendritic Cells Are Involved in Enhancing Herpes Simplex Virus Type 1 Latency
J. Virol.,
October 15, 2008;
82(20):
9870 - 9879.
[Abstract]
[Full Text]
[PDF]
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S. Vempati, C. Reindl, U. Wolf, R. Kern, K. Petropoulos, V. M. Naidu, C. Buske, W. Hiddemann, T. M. Kohl, and K. Spiekermann
Transformation by Oncogenic Mutants and Ligand-Dependent Activation of FLT3 Wild-type Requires the Tyrosine Residues 589 and 591
Clin. Cancer Res.,
July 15, 2008;
14(14):
4437 - 4445.
[Abstract]
[Full Text]
[PDF]
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H. Karsunky, M. A. Inlay, T. Serwold, D. Bhattacharya, and I. L. Weissman
Flk2+ common lymphoid progenitors possess equivalent differentiation potential for the B and T lineages
Blood,
June 15, 2008;
111(12):
5562 - 5570.
[Abstract]
[Full Text]
[PDF]
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S. Chumsri, W. Matsui, and A. M Burger
Therapeutic Implications of Leukemic Stem Cell Pathways
Am. Assoc. Cancer Res. Educ. Book,
April 12, 2008;
2008(1):
397 - 406.
[Abstract]
[Full Text]
[PDF]
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A. Sallmyr, J. Fan, K. Datta, K.-T. Kim, D. Grosu, P. Shapiro, D. Small, and F. Rassool
Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair: implications for poor prognosis in AML
Blood,
March 15, 2008;
111(6):
3173 - 3182.
[Abstract]
[Full Text]
[PDF]
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Introduction
References
Introduction