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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 2760-2770
REVIEW ARTICLE
The SCL Gene: From Case Report to Critical Hematopoietic Regulator
By
C. Glenn Begley and
Anthony R. Green
From the Walter and Eliza Hall Institute of Medical Research and the
Rotary Bone Marrow Research Laboratories, Royal Melbourne Hospital,
Parkville, Victoria, Australia; and the Department of Haematology,
University of Cambridge, Cambridge UK.
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BEGINNING AT THE BEDSIDE: A CASE OF T-CELL LEUKEMIA |
THIS STORY BEGINS with a seminal case
report describing a 16-year-old boy who presented with acute
lymphoblastic leukemia (ALL).1 He had an elevated white
blood cell (WBC) count, thymic enlargement, and leukemic cells with an
early T-cell phenotype (CD2 and CD7 positive; CD3, CD4 and CD8
negative). Standard chemotherapeutic agents failed to induce remission,
and treatment commenced with the adenosine deaminase inhibitor
2'-deoxycoformycin. Over the next 7 days, the leukemic cells
underwent an abrupt and dramatic transformation. The lymphoid leukemic
cells acquired morphological features of myeloid cells, gained myeloid
antigens, and lost CD7 expression. Unfortunately, the patient died of
extensive tissue infiltration with cells of promyelocyte morphology.
This "stem cell leukemia" phenotype was also evident in vitro
because exposure of the leukemic cells to 2'-deoxycoformycin
stimulated multi-lineage differentiation. Before and after the
phenotypic conversion, the leukemic cells carried a translocation
between chromosome 1p32-33 and the T-cell receptor (TCR)  / locus
on chromosome 14q11.
The investigators established a cell line that carried the same
chromosomal translocation and recapitulated the stem cell phenotype
during in vitro culture.2 They further showed that other
cases of ALL, with a similar cell surface phenotype, did not show this
specific cytogenetic abnormality.3 Although rearrangements of chromosome 1p32-33 are now recognized to occur frequently in T-cell
ALL, there have been no reports of these leukemias being treated with
similar agents, nor reports of such a striking morphological conversion. Based on what is now known about the molecular genetics of
this event, it seems reasonable to speculate that other cases may
respond in a similar manner and that ultimately this might be exploited
for therapeutic advantage. However, there is still no clear explanation
for the mechanism by which 2'-deoxycoformycin induced this
dramatic change.
At that time, the recent successes in identifying genes involved in
B-cell tumors as a result of their translocation into the Ig gene loci
inspired a search for the gene responsible for the stem cell phenotype.
By analogy with B-cell tumors, it seemed likely that the responsible
gene was located on chromosome 1 and, as a result of the translocation
into the TCR locus, it was aberrantly activated when transcription of
the TCR locus was attempted. However, analysis of the translocation
first required characterization of the TCR and loci and
recognition that the locus contained the locus embedded within
it.4-8 Once probes to the human TCR locus became
available, the translocation breakpoint was isolated and a new gene on
chromosome 1 was identified.9,10 The name "stem cell
leukemia" gene or SCL was assigned, a name that has turned out to be
remarkably appropriate given the essential function of this gene in
normal hematopoietic stem cells (see below). The same gene was
independently identified by several other groups.11-13
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RECONSTRUCTING THE CRIME: A CASE OF MISTAKEN IDENTITY |
The t(1;14) translocation was the first example of what has since
transpired to be a common theme in a significant proportion of T-ALL
cases; the aberrant activity of recombinase enzymes with abnormal
expression of SCL as a result.
The leukemic cells were captured at a very early stage of T-cell
development and frozen while in the process of rearranging/deleting both their TCR loci. On one chromosome 14 the cells were caught in
the process of attempting to delete the entire TCR locus.14 Deletion of the TCR locus is a necessary
prerequisite for TCR rearrangement15 and although this
transient intermediate state had been predicted to occur (ie, deleted but incomplete rearrangement),16 it had not
actually been previously observed.
The second chromosome 14 was the site of the translocation
event.9 Here the recombinase enzymes had successfully
juxtaposed two TCR diversity (or D region) genes and completed the
required excision of the intervening DNA. However, during or
immediately after this event, chromosome 1 had been inadvertently
involved in this otherwise normal recombination process. The presence
of additional, nontemplated nucleotides provided circumstantial
evidence implicating enzymes such as terminal deoxytidyl transferase
(TDT) as also being active at that moment.
There are mitigating circumstances that in part explain the
"error" on the part of the recombinase enzymes. The recombinases normally recognize specific DNA sequences that flank the segments of
DNA to be rearranged. These serve as specific signals that allow the
enzymes to correctly identify and juxtapose segments of DNA in the
process of assembling a functional TCR (or Ig) gene. Very similar
sequences are present in several regions of the human SCL gene, but
intriguingly are not seen in equivalent regions of the mouse
gene.17-19 Their normal function in the human SCL gene, if
any, is unknown. However, the presence of "signal-sequences" in
the human SCL gene does provide an explanation for the case of mistaken
identity in this chromosomal translocation. There is a second reason
that perhaps also partly explains this event. It is now known that SCL
is crucially important at the earliest stages of hematopoietic stem
cell development and differentiation. Therefore, the SCL gene was
likely to be hypomethylated in an "open," chromatin
configuration, thus making it vulnerable to the recombinase
enzymes.20
This patient's translocation disrupted the 3' untranslated
region of the SCL gene, preserving the SCL protein intact and thus allowing production of the normal protein to be inappropriately regulated by elements within the TCR locus. As a consequence, SCL
expression was readily detected within the leukemic T cells while SCL
is not detected in the vast majority of normal
thymocytes.10,21-24
Other investigators had also noted rare cases of T-ALL with
translocations between chromosomes 1 and 14 occurring in about 3% of
cases,25-27 and Bernard et al13 went on to show
that SCL was also dysregulated in some of these cases. At least 10 chromosomal translocations involving SCL have since been defined, with
the majority of these occurring into the TCR /
locus.12,28-31 However, translocations involving SCL and
chromosomes 3, 5, and 7 (the TCR  locus) have also been
documented.32-34 These translocations all have in common
the errant expression of SCL in a T-cell environment. In addition, the
fact that breakpoints within the SCL gene lie at the site of signal
sequences strongly suggests that the recombinase enzyme complex is
again likely to be the primary culprit. Because of the frequent
involvement of SCL in leukemias with a T-cell phenotype, the names
TCL-5 and TAL-1 were also proposed.11,12,30
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VARIATIONS ON THIS THEME: SCL DYSREGULATED BY UPSTREAM DELETIONS
RESULTING FROM ABERRANT RECOMBINASE ACTIVITY |
In addition to chromosomal translocations, there is a second mechanism
by which the SCL gene can be disrupted and aberrantly activated in
leukemic T lymphocytes. This involves deletions of approximately 90 kb
of DNA from chromosome 1 that brings SCL under the control of the
upstream, ubiquitously expressed SIL (for SCL interrupting locus)
gene.35-38 Again, recombinase enzymes are the primary
suspect in the genesis of the SIL/SCL deletions (also known as
Tald): the presence of specific recombination signal
sequences in both the SIL and SCL genes ensure that a limited number of
SIL/SCL deletional events are seen recurrently in independent leukemic samples. Although this "limited number" could theoretically be as
high as 18, with 3 recombination sites observed within the SIL gene and
at least 6 different recombination sites observed within SCL, only two
types of deletion are commonly observed. The SIL/SCL deletional event
in T-cell leukemia occurs with a frequency estimated to be between 6%
and 26% of cases.35,39-43 The generation of unique
sequences at the site of the SIL/SCL junction can serve as a useful
leukemia-specific and patient-specific marker for polymerase chain
reaction (PCR)-based techniques to detect residual leukemic
cells.44 More recently it was proposed that SCL may be
aberrantly expressed in up to 60% of childhood T-ALL samples in many
cases without detectable rearrangements of the gene.45 This
potentially provided an explanation for earlier studies that failed to
identify a significant clinical, phenotypic, or prognostic subgroup of
T-ALL associated with SCL rearrangement. However, it has been suggested
that SCL expression observed in the absence of SCL rearrangements was
probably caused by contamination of the leukemic blasts with normal
hematopoietic cells.46
Despite the lack of a clearly distinct clinical subgroup of T-ALL
associated with SCL rearrangement, there is one characteristic that is
highly correlated with the presence of the SIL/SCL deletion; deletion
of one or both TCR gene(s). Therefore, SCL rearrangements are
observed predominantly, but not exclusively, in CD3 positive, TCR
/ positive T-ALL.41,42,47 The striking
concordance with deletion of the TCR locus, a prerequisite for TCR
rearrangement, raises the possibility that SCL may even play a role
in regulating deletion of the TCR loci and in commitment to the TCR
/ T-cell lineage.20,47
Although the structural alterations of the SCL gene are seen in T-ALL,
they are not seen in B-lineage ALL, acute myeloid leukemia (AML),
T-cell non-Hodgkin's lymphomas, or in a range of other solid
tumors.43,44,48 Although expression of SCL has been observed in samples of AML and may even correlate with poor
outcome,49 this probably reflects malignant transformation
of myeloid progenitor/stem cells that normally express
SCL.23,24,50
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ILLICIT LIAISONS: HOW DOES SCL CONTRIBUTE TO T-ALL? |
Although the genetic lesions outlined above result in ectopic
expression of SCL in a T-cell environment, the precise mechanism(s) by
which this transcription factor contributes to leukemia development remains uncertain.
There is clear evidence that SCL can provide a proliferative advantage
to cells in a number of different contexts. Expression of antisense SCL
in a multipotent human cell line caused a significant decrease in
cellular proliferation, decreased progression of cells through the cell
cycle, and resulted in a 50-fold decrease in self-renewal potential,
thus suggesting that SCL normally influences these
functions.51 Similarly, aberrant SCL expression in a T-cell environment increased clonogenic ability.52 In murine
myeloid cells, retrovirally enforced SCL expression allowed cells to
"escape" differentiation induction and overcome
growth-factor-induced suppression of clonogenicity.53-55
Likewise, SCL expression as a consequence of an insertion of a
retroviral-like element, an intra-cisternal A particle, conferred a
growth advantage on myeloid cells and resistance to
differentiation-inducing agents.56,57 Thus, in these
various contexts enforced SCL expression stimulates proliferation and
opposes differentiation. Within a different cellular context, erythroid
cells, enforced SCL expression also enhances cell proliferation, although in this setting differentiation is
stimulated.58-60 In addition to its action to stimulate
proliferation in a variety of contexts, SCL expression delayed
apoptosis55,61,62; again, this action may depend on the
cell type in which SCL is acting.55 Therefore, as with
other oncogenes, it is likely that SCL contributes to leukemogenesis by
multiple mechanisms that include an increase in proliferation, cell
cycling, and self-renewal potential with a decrease in cell death.
These actions of SCL translate into increased leukemia development and
subsequent death in a variety of animal models. In some transgenic
models expression of SCL alone did not cause leukemia to occur,
presumably as a consequence of the regulatory elements that were used
to direct SCL expression.63-65 However, several groups have
demonstrated cooperation in vivo between SCL and a variety of
additional genes including ABL,52 casein kinase
II,66 p53,62,67 and RAS.67 Whether
any of these cooperating genes contribute to human T-ALL is unclear.
However, SCL also collaborates with the LIM domain proteins LMO-1 and
LMO-2 to generate tumors.64,65 This interaction is
particularly intriguing because SCL, LMO-1, and LMO-2 are implicated in
human T-ALL. However, all the mouse models suggest that additional
events are still needed, and in the context of SCL and the LIM domain
proteins, defects in the DNA mismatch repair gene MSH2 are probably
important.68
The biochemical basis for the tumorigenic cooperation described above
remains unclear. However, it is known that SCL interacts with the
products of the E2A gene69-71 and related
proteins72 to form heterodimeric DNA-binding complexes. The
heterodimer can form part of a larger protein complex in which LMO-2
acts as a molecular bridge between the zinc finger transcription factor GATA-1 and the SCL/E2A heterodimer (Fig
1).73,74 Using a chromatin immuno-precipitation approach,
Cohen-Kaminsky et al75 have recently identified a novel
gene of unknown function that is expressed in erythroid cells and that
is directly regulated by a complex containing SCL and GATA-1. Although
these interactions have been characterized primarily in erythroid
cells, where SCL is normally expressed, a large protein complex occurs
in T cells, but with altered DNA binding specificity.76 The
existence of such multi-component protein complexes is an emerging
theme in the area of transcriptional regulation. The constituents of
the complex are likely to vary in different cell types, differentiation
states, or cell cycle stages, perhaps explaining in part the
multiplicity of functions ascribed to SCL and other transcription
factors.
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| Fig 1.
(A) SCL forms part of a multiprotein complex. SCL
normally interacts with other transcription factors in erythroid cells
to form a multiprotein complex that contains transcription factors such
as GATA-1, LMO-2, LDB-1, and E2A proteins.74 As a result,
"Gene A" is appropriately regulated. The precise stoichiometry of
the complex is not known. (B and C) Models for the leukemogenic effect
of SCL expression in T cells. (B) The leukemogenic effect of ectopic
SCL expression in T cells may involve aberrant activation of target
genes (Gene B), perhaps by a complex involving additional bHLH proteins
(eg, X and Y).76 (C) Alternatively ectopic SCL expression
may sequester E2A and/or other T-cell proteins (eg, Z), thereby
upregulating or downregulating expression of their normal target genes
(Gene C).
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The leukemogenic effect of SCL expression in T cells may reflect either
activation of target genes that should normally be silent, or
alternatively the sequestration of other components of the
multi-protein complex (Fig 1). Several lines of circumstantial evidence
support the latter view: (1) SCL can sequester E2A proteins, thereby
inhibiting transactivation of genes that normally require E2A
proteins.77-79 (2) Mice lacking a functional E2A gene
develop T-cell tumors.80 (3) As mentioned above, casein
kinase II cooperates with SCL to hasten T-cell tumors,66
and casein kinase II is also known to inhibit activity of proteins
derived from the E2A gene.81 (4) Mice carrying an SCL
transgene lacking its transactivation domain still develop lymphoid
tumors65 (although it remains possible that SCL/E2A
heterodimers aberrantly transactivate critical target genes via the E2A
transactivation domain).
If SCL does act as a molecular sink in T-ALL, one would predict that
this property would not be unique to SCL and that other transcription
factors capable of interacting with E2A proteins would also be
leukemogenic if ectopically expressed in T cells. The proteins LYL-1
and TAL-2 proteins share this characteristic and are indeed involved in
translocations in T-ALL, but only rarely.82 Therefore, the
particular prevalence of SCL rearrangements in T-ALL probably reflects
the presence of the specific signal sequences in the human SCL gene
that are recognized by the recombinase complex and dictate the site of
translocation and rearrangement events.
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JEKYLL AND HYDE: SCL NORMALLY FUNCTIONS AS A CRITICAL REGULATOR OF
HEMATOPOIESIS |
Given the unusual phenotype of the leukemic cells from which SCL was
first identified, it seemed possible that the protein encoded by the
SCL gene would also prove an important molecule in normal hematopoietic
cells. The first evidence that this was the case came from analysis of
the amino acid sequence for the predicted SCL protein.9 Two
important domains within the protein were immediately apparent. One
domain is a helix-loop-helix (HLH) region that is common to a large
family of functionally important transcription factors. This region
allows SCL to heterodimerize with E12 and E47, products of the E2A gene
and themselves HLH transcription factors. In fact, the E2A gene [which
is involved in the t(1;19) translocation in human B-ALL] was a
founding member of the HLH family along with C-MYC [involved in the
t(8;14) translocation of Burkitt's lymphoma], MYO-D (an important
regulator of muscle differentiation), and daughterless (a
Drosophila gene involved in sex determination).83
The second conspicuous domain within the SCL protein is a basic region,
which is also present in many other HLH proteins: the SCL/E2A
heterodimer binds DNA using the basic domains present within these
proteins.84 The site on the DNA to which the SCL/E2A heterodimer binds conforms to an "E-box" motif, which is also common to other proteins of the HLH class.83,85
A role for SCL in the regulation of normal hematopoiesis was suggested
by its normal expression pattern; SCL is restricted to hematopoietic
cells, endothelial cells, the central nervous system, and embryonic
skeleton.23,86,87 Within the hematopoietic compartment, SCL
is normally expressed within erythroid cells, mast cells,
megakaryocytes, and progenitor/"stem"
cells.10,21-24,50
The first clue to a normal function of the SCL protein came from
antisense experiments showing that SCL regulates proliferation and
self-renewal in a multipotent hematopoietic cell line.51 A
positive role for SCL in erythroid differentiation was suggested by the
observation that SCL mRNA levels increased during erythroid differentiation induced either by chemicals or
erythropoietin,22,23,50,88-90 although a concurrent
decrease in levels of SCL protein implies additional levels of
control.91 A more direct role for SCL in erythroid
differentiation was provided by gene delivery experiments where
enforced expression of SCL enhanced erythroid differentiation of
hematopoietic cell lines.58,90 Conversely, as cells
differentiated along the myeloid/macrophage pathway, levels of SCL mRNA
and protein decreased, becoming essentially
undetectable.50,53,54,90,92 The decrease in SCL expression
not only accompanies macrophage differentiation, but is also necessary
because enforced SCL expression prevents macrophage differentiation
from proceeding normally.53,54,90 These results in cell
lines have recently been confirmed and extended using normal human
CD34-positive "stem" cells. In these cells, retrovirally directed
SCL expression enforces and hastens erythroid differentiation and also
directs megakaryocytic differentiation, with less striking effects on
the myeloid compartment.59,60
Dramatic confirmation that the SCL gene encodes a vital stem cell
regulator came from studies in which SCL function was destroyed (Fig 2). This was achieved using gene
targeting in embryonic stem (ES) cells to derive SCL-null mutant
animals ("knock-out" mice). Mice lacking SCL function died at
about 8.5 days of embryonic development (E8.5) with a complete failure
of yolk sac hematopoiesis,93,94 suggesting that SCL is
crucial for the generation of hematopoietic cells in the early embryo
("primitive hematopoiesis"). SCL plays a similar essential role
in adult, "definitive" hematopoiesis. After injection of
SCL-null ES cells into blastocysts, analysis of the resulting chimeric
animals showed the complete failure of the SCL-null ES cells to give
rise to hematopoietic cells in the adult animals, although the mutant
ES cells did contribute to all other tissues examined.95,96
Furthermore, these SCL-null ES cells failed to give rise to
hematopoietic cells during in vitro culture and failed to express
hematopoietic-specific genes.97 Taken together, these
observations show that SCL plays a critical role in the generation
and/or subsequent behavior of pluripotent hematopoietic stem cells.
This role is "cell-autonomous," and occurs within the stem cell
itself. These results also predict that normal SCL-expressing
progenitors should function as multipotent cells, displaying the
ability to generate hematopoietic cells committed to multiple lineages.
This prediction has recently been confirmed using a gene-targeting
approach; a marker gene (Lac-Z) was introduced into the SCL locus,
thereby allowing the isolation of SCL-expressing cells for functional
analysis.98 These results confirm the status of SCL as a
"master regulator" for hematopoiesis.99
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| Fig 2.
SCL is required for development of hematopoietic stem
cells. (A) Wild type (+/+) and SCL mutant ( /) mouse embryos.
Note the red-brown coloration of the normal embryo due to blood within
the fetal liver and vessels. This is absent in the mutant which also
has a runted appearance. (B) Histological section through the mouse
yolk sac with blood islands (arrows) present in the wild-type and
lacking in the SCL mutant yolk sac. (C) Histological section through
the embryo showing hematopoietic cells in the paired dorsal aortae in
the wild type (arrows) and the absence of these cells in the dorsal
aortae of the SCL mutant (arrows). (Reprinted with permission from Robb
L, Lyons I, Li R, Hartley L, Kontgen F, Harvey RP, Metcalf D, Begley
CG: Absence of yolk sac hematopoiesis from mice with a targeted
disruption of the scl gene. The Proceedings of the National
Academy of Sciences, U.S.A., vol 92, p 7075, 1995. Copyright 1995 National Academy of Sciences, U.S.A.93)
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The results with SCL are remarkably similar to those seen when the
LMO-2 gene is destroyed. LMO-2 null animals also lack any detectable
hematopoietic cells within the yolk sac and embryo, and die at about
E8.5.100 Similarly, LMO-2 null ES cells fail to contribute
to adult hematopoiesis,101 thus reinforcing the parallels
between SCL and LMO-2. In addition to interacting in erythroid and some
leukemic T cells, it therefore seems likely that SCL and LMO-2 are
components of a critical multiprotein complex present in hematopoietic
stem cells.
Thus, the phenotype of the initial stem cell leukemia implied SCL was
capable of regulating hematopoietic differentiation in the leukemic
cells. Pursuit of this early clue has unmasked a master gene which
functions as a critical regulator of hematopoiesis.
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HIDDEN TALENTS: SCL ALSO CONTROLS HEMANGIOBLAST FORMATION AND
ENDOTHELIAL DEVELOPMENT |
Given the crucial function of SCL within hematopoietic stem cells, the
expression of SCL within endothelial cells raised the possibility that
SCL could also function within an even more primitive cell, the
putative common hematopoietic and endothelial precursor, the
hemangioblast. There is a long-recognized, close relationship between
the development of blood and endothelium, suggesting that they may well
share a common precursor. Both cell types emerge at a similar time
during the formation of the yolk sac blood islands,102-104 and early intra-embryonic sites of hematopoiesis and are closely associated with vessels.105-111 In addition, a number of
molecules are expressed in both endothelium and in hematopoietic
progenitors including CD34.112,113 Furthermore, mice
lacking the early endothelial marker Flk-1 display a defect in both
hematopoietic cells and vasculature,114 and Flk-1 appears
to play an important and cell-autonomous role in the formation of both
lineages.115 Consistent with this concept VEGF, the ligand
for Flk-1, can stimulate the generation of hematopoietic cells from ES
cells116 and single Flk-1 positive avian cells can generate
either hematopoietic or endothelial cells in vitro.117
Moreover, in the zebrafish mutant cloche, the numbers of both
endothelial and hematopoietic cells are severely
reduced.118 These studies are all consistent with the
notion of a common precursor for hematopoietic and endothelial cells.
Several lines of evidence suggest a functional role for SCL in
endothelial cell development. SCL is expressed in normal
endothelium86,119 and in SCL-null animals there is a defect
in the development of yolk sac blood vessels with the failure of
formation of large vitelline vessels.93 This was shown to
reflect a primary consequence of SCL loss in elegant transgenic
experiments that rescued the hematopoietic, but not the vascular
defect, in the SCL-null mice.120 Furthermore, in the
zebrafish mutant cloche, both the endothelial and hematopoietic
defects are partially rescued by ectopic expression of
SCL.121
Direct evidence for a role for SCL in hemangioblast formation has been
reported by Gering et al122
(Fig 3). SCL was coexpressed with Flk-1 in
presumptive hemangioblasts within early postero-lateral mesoderm of
zebrafish embryos. Ectopic expression of SCL mRNA during zebrafish
development resulted in an expansion of hematopoietic and endothelial
precursors at the expense of somitic and pronephric duct tissues. Taken
together, these data show that SCL is capable of specifying or
directing hemangioblast development from early mesoderm, and underline
the striking similarities between the role of SCL in
hematopoiesis/vasculogenesis and the function of other HLH proteins in
muscle and neural development.123,124
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| Fig 3.
SCL specifies hemangioblast development from early
zebrafish mesoderm. Appearance of uninjected zebrafish embryos (a) and
embryos injected with SCL mRNA at the 2-4 cell stage (b). SCL injected
embryos developed a marked excess of hemoglobinized blood cells
(arrowhead), a striking absence of blood circulation despite a beating
heart and an abnormally curved axis. In situ hybridization experiments
with SCL alone (c) or SCL and Flk-1 (d) showed a marked increase in
cells coexpressing both endogenous SCL and Flk-1 in SCL-injected
embryos. This increase was often unilateral (as illustrated in this
figure), because the injected mRNA was frequently localized to one half
of an embryo. NT, neural tube; NC, notochord; SM, somitic mesoderm; LM,
lateral mesoderm. (Reprinted from Gering M, Rodaway ARF, Göttgens
B, Patient RK, Green AR: The SCL gene specifies haemangioblast
development from early mesoderm. The EMBO Journal, vol 17, p
4029, 1998, by permission of Oxford University Press.122)
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It is interesting to contrast the loss of function phenotype, in which
endothelial cells develop but fail to contribute normally to vessel
formation, with the gain of function experiments described above. These
results are consistent with previous studies of HLH proteins in
myogenesis and neurogenesis, suggesting a cascade of HLH proteins that
may have overlapping functions and expression patterns.123,124 In the case of SCL, functional redundancy
with related HLH proteins may explain the relatively normal development of endothelial cells in SCL null mice.
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DEUS EX MACHINA: WHAT REGULATES THE REGULATOR? |
Multiple tiers of regulation.
Although multiple mechanisms exist and at different levels, to ensure
that the critical functions of SCL are tightly controlled, these
mechanisms and their significance are poorly understood. However, the
importance of these mechanisms is amply demonstrated when they go awry
in the T lymphocyte.
At the level of SCL protein, there is a requirement for HLH partner
proteins such as E12 and E47. Additional control is provided via a
subgroup of HLH proteins, the prototypic example of which is Id. These
HLH family members lack a DNA-binding basic domain and thereby isolate
other HLH proteins in inactive complexes.125 Moreover, the
SCL protein itself exists in several different forms as a result of
multiple sites of protein initiation within the SCL
gene.17-19,28,126-128 These proteins can occur in a
cell-type-specific manner and may differ in their ability to
transactivate downstream genes. Regulation of protein
turnover91 and phosphorylation on serine127 are
probably also important in regulating the function of SCL protein.
Signaling pathways.
Several lines of evidence suggest links between SCL and a number of
signal transduction pathways. During early development the formation of
blood progenitors is thought to be initiated by growth factors,
including bone morphogenetic protein 4 (BMP-4). During hematopoietic
development in Xenopus, SCL expression is induced by BMP-4 and
its expression is inhibited by a dominant-negative BMP-4
receptor.129 However, the precise position of SCL within the hierarchy of transcription factors modulated by BMP-4 is not known.
In the context of adult hematopoiesis, SCL has been linked to growth
factor signaling pathways that suggest a "downstream" role for
SCL. During erythroid differentiation, levels of SCL increase in
response to stem cell factor130,131 and
erythropoietin.88,89 Conversely, levels of SCL mRNA and
protein decrease during growth-factor-induced macrophage
differentiation.53,54 SCL is also a target for MAP kinases,
including ERK-1.132
By contrast, antisense and dominant-negative SCL constructs reduced
levels of c-kit (the receptor for stem cell factor) and SCL
transactivated the c-kit promoter.134 These data raise the possibility that c-kit is regulated by SCL.
These observations are relevant to current views of hematopoietic stem
cell behavior and lineage commitment. Several lines of evidence suggest
that multiple components of distinct differentiation programs may be
primed and undergo low-level transcription within individual
multipotent stem cells.135 Commitment to a particular lineage may result from poorly understood and possibly stochastic processes that result in a single program becoming dominant and reinforced with competitive feedback loops. Transcription factors play
a pivotal role in these processes. Thus, upregulation of c-kit or other
growth factor receptors by SCL may modulate the behavior of multipotent
cells and, as part of a self-sustaining feedback loop, participate in
the lineage-commitment process.
Cis-acting elements.
The functions of many transcription factors hinge on their cellular
context, the presence or absence of interacting proteins, and the
accessibility of potential target genes. Therefore, the biological
function of a given transcription factor is likely to depend critically
upon its pattern of expression. This reasoning has focused attention on
the cis-acting elements that regulate SCL transcription.
Characterization of SCL regulatory elements that drive expression in
hemangioblasts or multipotent progenitors will illuminate the molecular
basis for the formation of these cell types and also provide important
tools for experimental or therapeutic manipulation of hematopoietic
stem cells.
Two promoters in alternative 5' exons have been identified in
both murine and human SCL genes,17,19,136-138 together with
a third promoter within the body of the gene, the normal function of
which remains unclear.133 Both 5' promoters exhibit
lineage restricted activity. Promoter 1a is regulated by GATA-1, SP1, and SP3, and is active in transient reporter assays in erythroid and
mast cells.58,136,137,139 Promoter 1b is regulated by PU-1, SP1, and SP3, and is active in mast and primitive myeloid
cells.138,139 Thus, in committed hematopoietic lineages,
SCL appears to be regulated at least in part by a transcription factor
with a pivotal role in erythroid cells (GATA-1) and by a critical
myeloid transcription factor (PU-1).
However, although these promoters recapitulate aspects of the
lineage-restricted pattern of SCL expression in transient reporter assays, they are not sufficient to direct reporter gene expression once
integrated in chromatin.138 This observation stimulated a
search for distant regulatory elements ("enhancers") in the vicinity of the SCL gene. Therefore, a systematic survey of chromatin structure surrounding the SCL locus was undertaken140,141
and resulted in identification of a number of enhancers active in both
transient and stable transfection assays.141 More recently, transgenic assays have been used to study the activities of these elements and have identified spatially distinct enhancers that mimic
components of normal SCL expression in endothelium, midbrain, hindbrain/spinal cord, and hematopoietic progenitors (A. Sinclair, M.-J. Sanchez, and A.R. Green, unpublished data, 1998).
One element is particularly exciting because it appears to target
hematopoietic progenitors throughout ontogeny.
| |
UNRESOLVED ISSUES |
SCL is clearly pivotal for normal hematopoiesis and vasculogenesis and
is also likely to have a critical role in the nervous system. A
plethora of questions remain unanswered. How does SCL induce an
undifferentiated mesodermal cell to become a hemangioblast and then a
multipotent hematopoietic stem cell? Does SCL perform the same role in
different classes of hematopoietic stem cells throughout ontogeny? What
is the role of SCL in the nervous system? Why is ectopic SCL expression
leukemogenic in T-cell progenitors?
Answers to these and other questions are likely to require advances in
at least three areas. First, we need to understand the significance of
the multiprotein complexes that include SCL. How do the complexes
differ in distinct cell types and what are the functional consequences
of those differences? Second, it seems likely that different complexes
will activate distinct target genes, and so it will also be essential
to identify direct target genes downstream of SCL in different
SCL-expressing cell types. Only in this way will we be able to put
molecular flesh onto our skeletal ideas of SCL's various functions.
Third, how is SCL itself regulated? What triggers SCL expression in
early mesoderm and therefore results in hemangioblast specification?
How is SCL downregulated during differentiation along specific
hematopoietic lineages, and is the modulation cause or consequence? Is
there an SCL enhancer that can be used to target hematopoietic stem
cells? At the current rate of progress, we should not have long to wait
for some answers. Hopefully this will lead back to the bedside with new
approaches to the manipulation of hematopoiesis and the treatment of
T-ALL.
| |
FOOTNOTES |
Submitted October 6, 1998; accepted December 17, 1998.
Supported by The Wellcome Trust, Leukaemia Research Fund (UK), Kay
Kendall Leukaemia Fund (UK), Medical Research Council (UK), National
Health and Medical Research Council (Canberra), Anti-Cancer Council of
Victoria, and the Bone Marrow Donor Institute, Melbourne.
Address reprint requests to C. Glenn Begley, MD, PhD, the
Walter and Eliza Hall Institute of Medical Research and the Rotary Bone
Marrow Research Laboratories, PO Royal Melbourne Hospital, Parkville,
Victoria, Australia 3050.
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[Abstract]
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T. Portis and R. Longnecker
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PNAS,
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[Abstract]
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E. Lecuyer, S. Herblot, M. Saint-Denis, R. Martin, C. G. Begley, C. Porcher, S. H. Orkin, and T. Hoang
The SCL complex regulates c-kit expression in hematopoietic cells through functional interaction with Sp1
Blood,
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[Abstract]
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[Abstract]
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[Abstract]
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B. Gottgens, L. M. Barton, M. A. Chapman, A. M. Sinclair, B. Knudsen, D. Grafham, J. G.R. Gilbert, J. Rogers, D. R. Bentley, and A. R. Green
Transcriptional Regulation of the Stem Cell Leukemia Gene (SCL) --- Comparative Analysis of Five Vertebrate SCL Loci
Genome Res.,
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[Abstract]
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M. Cambot, S. Aresta, B. Kahn-Perles, J. de Gunzburg, and P.-H. Romeo
Human Immune Associated Nucleotide 1: a member of a new guanosine triphosphatase family expressed in resting T and B cells
Blood,
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[Abstract]
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S. Tsuzuki and T. Enver
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Blood,
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[Abstract]
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Engraftment and Differentiation of Human Metanephroi into Functional Mature Nephrons after Transplantation into Mice Is Accompanied by a Profile of Gene Expression Similar to Normal Human Kidney Development
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Y. Peng and N. Jahroudi
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[Abstract]
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S. Herblot, P. D. Aplan, and T. Hoang
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B. Falini and D. Y. Mason
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[Abstract]
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U. Thorsteinsdottir, A. Mamo, E. Kroon, L. Jerome, J. Bijl, H. J. Lawrence, K. Humphries, and G. Sauvageau
Overexpression of the myeloid leukemia-associated Hoxa9 gene in bone marrow cells induces stem cell expansion
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[Abstract]
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M.-J. Sanchez, E.-O. Bockamp, J. Miller, L. Gambardella, and A. R. Green
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Development,
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[Abstract]
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E. V. Rothenberg
Mapping of complex regulatory elements by pufferfish/zebrafish transgenesis
PNAS,
June 5, 2001;
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[Full Text]
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L. M. Barton, B. Gottgens, M. Gering, J. G. R. Gilbert, D. Grafham, J. Rogers, D. Bentley, R. Patient, and A. R. Green
Regulation of the stem cell leukemia (SCL) gene: A tale of two fishes
PNAS,
May 24, 2001;
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101532998.
[Abstract]
[Full Text]
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B. Göttgens, J. G.R. Gilbert, L. M. Barton, D. Grafham, J. Rogers, D. R. Bentley, and A. R. Green
Long-Range Comparison of Human and Mouse SCL Loci: Localized Regions of Sensitivity to Restriction Endonucleases Correspond Precisely with Peaks of Conserved Noncoding Sequences
Genome Res.,
January 1, 2001;
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[Abstract]
[Full Text]
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T. Blake, N. Adya, C.-H. Kim, A. C. Oates, L. Zon, A. Chitnis, B. M. Weinstein, and P. P. Liu
Zebrafish homolog of the leukemia gene CBFB: its expression during embryogenesis and its relationship to scl and gata-1 in hematopoiesis
Blood,
December 15, 2000;
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[Abstract]
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A. Kappel, T. M. Schlaeger, I. Flamme, S. H. Orkin, W. Risau, and G. Breier
Role of SCL/Tal-1, GATA, and Ets transcription factor binding sites for the regulation of Flk-1 expression during murine vascular development
Blood,
November 1, 2000;
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[Abstract]
[Full Text]
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D. R. Bentley
Decoding the human genome sequence
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[Abstract]
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S. Tsuzuki, M. Towatari, H. Saito, and T. Enver
Potentiation of GATA-2 Activity through Interactions with the Promyelocytic Leukemia Protein (PML) and the t(15;17)-Generated PML-Retinoic Acid Receptor alpha Oncoprotein
Mol. Cell. Biol.,
September 1, 2000;
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[Abstract]
[Full Text]
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L. Vitelli, G. Condorelli, V. Lulli, T. Hoang, L. Luchetti, C. M. Croce, and C. Peschle
A Pentamer Transcriptional Complex Including tal-1 and Retinoblastoma Protein Downmodulates c-kit Expression in Normal Erythroblasts
Mol. Cell. Biol.,
July 15, 2000;
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[Abstract]
[Full Text]
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K. P. Anderson, S. C. Crable, and J. B. Lingrel
The GATA-E box-GATA motif in the EKLF promoter is required for in vivo expression
Blood,
March 1, 2000;
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1652 - 1655.
[Abstract]
[Full Text]
[PDF]
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C. Courtes, N. Lecointe, L. Le Cam, F. Baudoin, C. Sardet, and D. Mathieu-Mahul
Erythroid-specific Inhibition of the tal-1 Intragenic Promoter Is Due to Binding of a Repressor to a Novel Silencer
J. Biol. Chem.,
January 14, 2000;
275(2):
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[Abstract]
[Full Text]
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A. G. Elefanty, C. G. Begley, L. Hartley, B. Papaevangeliou, and L. Robb
SCL Expression in the Mouse Embryo Detected With a Targeted lacZ Reporter Gene Demonstrates Its Localization to Hematopoietic, Vascular, and Neural Tissues
Blood,
December 1, 1999;
94(11):
3754 - 3763.
[Abstract]
[Full Text]
[PDF]
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J Palis, S Robertson, M Kennedy, C Wall, and G Keller
Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse
Development,
January 11, 1999;
126(22):
5073 - 5084.
[Abstract]
[PDF]
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L. M. Barton, B. Gottgens, M. Gering, J. G. R. Gilbert, D. Grafham, J. Rogers, D. Bentley, R. Patient, and A. R. Green
From the Cover: Regulation of the stem cell leukemia (SCL) gene: A tale of two fishes
PNAS,
June 5, 2001;
98(12):
6747 - 6752.
[Abstract]
[Full Text]
[PDF]
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BEGINNING AT THE BEDSIDE:...
RECONSTRUCTING THE CRIME: A...