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Next Article 
Blood, Vol. 93 No. 7 (April 1), 1999:
pp. 2143-2148
Seed Versus Soil: The Importance of the Target Cell for
Transgenic Models of Human Leukemias
By
Peter Westervelt and
Timothy J. Ley
From the Division of Bone Marrow Transplantation and Stem Cell
Biology, Washington University School of Medicine, St Louis, MO.
 |
INTRODUCTION |
THE ASSOCIATION of several characteristic
chromosomal translocations with various subtypes of acute and chronic
myelogenous and lymphocytic leukemias has facilitated the cloning of a
number of unique leukemia-associated fusion genes. Characterization of these fusion genes has in turn led to the discovery of previously unrecognized genes. Some of these have now been extensively
characterized in vitro, and many encode transcription factors that play
important roles in normal hematopoietic development.1
Recently, the function of several leukemia-associated fusion genes has
been investigated using various transgenic murine systems.
Despite the generation of acute leukemias in some cases, inconsistent
results have made comparisons among different transgenic
models problematic. Consequently, fundamental questions remain
unanswered about the precise nature of the events leading to the
generation of acute leukemias, and the hematopoietic cell type(s) in
which such events can occur. The purpose of this perspective is to
discuss briefly the potential advantages and disadvantages inherent in
various transgenic approaches that are used to model
leukemias at the present time, and to discuss future applications of
these approaches for achieving a better understanding of the molecular
events leading to acute leukemia.
| |
WHAT IS THE TRANSFORMED HEMATOPOIETIC COMPARTMENT (THE CELLULAR
"SOIL") OF HUMAN MYELOID LEUKEMIAS? |
Bonnet and Dick2 have recently demonstrated that
transmission of human acute myeloid leukemias (AML) to nonobese
diabetic/severe combined immunodeficient (NOD/SCID) mice
requires transplantation of a phenotypically immature
CD34+/38 cell population that comprise a
small minority of circulating cells ("SCID-leukemia initiating cells
[SL-ICs]). These studies used primary leukemia cells from a variety
of AML French-American British (FAB) phenotypic subclassifications (M1,
M2, M3, M4, M5). However, cells from patients with the M3 subtype
(acute promyelocytic leukemia [APML]) were different, in that M3
SL-ICs were not present in any progenitor fraction (or in
unfractionated peripheral blood). These observations suggest that for
most AML subtypes, a relatively primitive cell is the target of
leukemic transformation, regardless of the extent and lineage of
differentiation observed in the majority of leukemic cells present in
the peripheral circulation. Given the inability to transplant the M3
subtype using the NOD/SCID system, however, this model cannot be
extended at present to include APML.2 Another study
attempted to define the transformed compartment in
APML.3 Fluorescence-activated cell sorting
(FACS) of primary APML cells was used to show that the APML-associated
fusion gene PML/RARA was expressed in
CD34/38+, but not
CD34+/38 cells, suggesting that in APML, the
transformation process may involve a more differentiated cell type than
the pluripotent progenitor and/or stem cell compartments implicated in
other myeloid leukemia subtypes.2,3
| |
CURRENT APPROACHES FOR TARGETING ONCOGENE EXPRESSION (THE
"SEED") TO SPECIFIC HEMATOPOIETIC COMPARTMENTS IN MICE |
To investigate the leukemogenic capacity of various leukemia-associated
fusion genes in vivo, murine transgenic models have been used. A
gain-of-function transgenic model for leukemogenesis should ideally
result in the expression of a specific potential oncogene, without
perturbing the expression of other endogenous mouse genes. It should
cause the transgene to be expressed in a tissue- and
development-specific fashion, mirroring the pattern observed in human
disease. The regulation of expression of the oncogene should be such
that normal hematopoiesis can occur before (or in parallel with) the
development of leukemia.
Among the currently available methods for generating gain-of-function
models of leukemia in vivo, "standard" transgenesis has been in
use for the longest period of time. This method involves microinjection
of transgene DNA into murine oocytes, which are subsequently implanted
into pseudopregnant female mice to generate transgenic offspring. The
transgene consists of two essential components: the cDNA of interest,
and genomic sequences linked to the transgene that regulate its pattern
of expression (for examples, see Fig 1).
Regulatory sequences may be those normally located near the gene of
interest itself, or may be derived from an unrelated gene whose
temporal and tissue-specific expression conforms to the pattern of
expression desired for the study of the transgene. With this approach,
transgene integration into the host genome is thought to be random. As
a result, the level and pattern of transgene expression may vary
significantly between different founders. Furthermore, random transgene
integration into the host genome may have unanticipated consequences on
the expression of normal mouse genes. For these reasons, phenotypic analyses require the characterization of multiple founder lines before
conclusions can be reliably drawn. Finally, extensive prior characterization of the linked regulatory sequences is required, to
ensure that all the elements essential for the expression of the target
gene are included. An advantage of the standard transgenesis approach
is that the differing levels of transgene expression among founders
affords an oppurtunity to study the effects of gene dosage, which may
be a critical parameter for the development of many leukemias.
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| Fig 1.
Regulatory sequences used to control cDNA expression in
various published murine APML models. cDNA sequences are represented as
open boxes. Cathepsin G coding exons, included downstream of the
PML/RARA or PLZF/RARA cDNAs, are represented by filled boxes. The 5'
untranslated regions of the respective targeting loci are represented
by hatched boxes. The remainder of the targeting loci (upstream
regulatory regions, intronic sequences, and 3' untranslated regions)
are represented by plain lines. The MRP8 targeting construct includes
3' untranslated sequences placed downstream of the inserted cDNA. The
CD11b targeting construct consists of upstream CD11b regulatory
sequence and an SV40 polyadenylation signal (shaded box) located
downstream of the cDNA. These representations are not drawn precisely
to scale.
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More recently, approaches using homologous recombination have been
employed to circumvent many of the problems inherent in standard
transgenesis (Fig 2). With this approach, a
fusion gene cDNA is targeted directly to a predefined locus in the
mouse genome, which is selected based on a desired pattern of
expression. The homologous recombination event is mediated by DNA arms
derived from the targeted murine locus. These arms flank the desired
site of transgene insertion, typically in the 5' untranslated region between the transcriptional and translational start sites. Targeting arms are placed upstream and downstream from the cDNA in the targeting construct, together with a selectable marker cassette (eg, PGK-neo) which facilitates the positive selection of stably transfected embryonic stem (ES) cell clones. ES cell clones that have the desired
homologous recombination event are expanded and microinjected into
murine blastocysts, which are implanted in pseudopregnant females to
generate chimeric offspring. These chimeras are then bred to wild-type
mice to transmit the targeted allele to the germline.
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| Fig 2.
Targeting an endogenous murine locus using homologous
recombination. Coding exons of the targeted locus are represented as
solid boxes. The cDNA of interest and PGK-neo selectable marker
cassette are represented as open boxes. Transcriptional start sites for
the targeted gene locus and PGK-neo selectable marker cassette are
indicated by arrows. The 5' untranslated region is represented by a
hatched box. LoxP sites used for CRE recombinase-mediated selection
cassette excision are represented as open ovals.
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There are several potential advantages of the "knock-in"
approach. Because a single transgene is inserted into the mouse genome at a discrete, predefined locus, variegation in transgene expression patterns among founder lines should be eliminated. In theory, the
expression pattern of the transgene should mirror that of the targeted
locus, because all regulatory elements will usually be left intact.
However, there are also potential problems with the knock-in
transgenesis approach. These include: (1) the requisite disruption of
one allele of the targeted locus, which can result in heterozygous
loss-of-function and may affect the ultimate phenotype, independent of
transgene expression. (2) Insertion of the transgene into the targeted
locus can potentially alter the desired regulation of the locus by
disrupting normally juxtaposed regulatory elements, or by introducing
new regulatory elements located within the transgene itself. (3) There
is compelling evidence that selectable marker cassettes can negatively
affect the expression of other nearby genes,4-9 as well as
that of the targeted gene itself (unpublished observations, June
1998) ("neighborhood effects"). This problem has
been successfully addressed by removal of the selectable marker in
targeted ES cell clones, using a recombinase-mediated
excision event (Fig 2)5,6,8,9 (and unpublished
observations, June 1998).
A variation of the "knock-in" approach has been used to evaluate
the role of various leukemia-associated fusion genes in murine leukemia
models. With this approach, the endogenous murine locus from the
upstream partner in the human leukemia-associated fusion gene is used
as the locus targeted for homologous recombination; the test cDNA is
inserted at a point in the endogenous locus corresponding to the
breakpoint. For example, Corral et al10 inserted the 3'
portion of a human AF9 cDNA into the murine MII locus in ES cells,
recreating the MII/AF9 fusion gene formed as a result of the human
acute lymphoblastic leukemia-associated translocation t(4;11), and
observed the generation of acute leukemias in chimeric mice. The
advantage of this approach is that it recreates almost exactly the
fusion gene as it occurs in human leukemia, since the regulatory
sequences used are those of the murine homologue of the upstream fusion
partner. The major potential disadvantage of this approach is that many
of the genes involved in leukemia-associated translocations may play
essential roles in early hematopoietic development or may be expressed
in nonhematopoietic tissues. By directing the expression of a
leukemia-associated fusion gene to all primitive hematopoietic cells,
normal hematopoiesis may be sufficiently disrupted as to result in
embryonic lethality, precluding analysis of its capacity to cause
leukemia. For example, when a portion of a human ETO cDNA was targeted
to the murine AML-1 locus, or a portion of a human MYH11 cDNA was
targeted to the CBF- locus, the resultant phenotypes in both
cases resembled those of the AML-1 and CBF- knockout
animals, respectively, suggesting a dominant negative effect of the
fusion gene on normal hematopoiesis.11,12
Another potential disadvantage of all the transgenic approaches
described above is that in each, the transgene is carried in the
germline of the transgenic animal, unlike in human leukemia, in which
the translocation resulting in the formation of the fusion gene is an
acquired mutation that occurs in somatic cells. To circumvent the
problem of universal expression of the cDNA of interest in
hematopoietic tissues, one alternative approach could use CRE-mediated
recombination in vivo. With this approach, LoxP sites
would be sequentially targeted in ES cells to the breakpoints in the
respective upstream and downstream fusion gene partners of interest.
Expression of CRE recombinase in a desired hematopoietic compartment
would be achieved by breeding these mice with a line in which a CRE
cDNA was expressed in that compartment (as discussed above) to recreate
the relevant chromosomal translocation by means of a somatic
recombination event. Although attractive in theory, such an approach
would ultimately depend on an intermolecular recombination event
between different chromosomes, which may or may not occur with
meaningful efficiency. Furthermore, the continuous expression of CRE
recombinase within the hematopoietic compartment could potentially lead
to unexpected recombination and/or other unwanted events.
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TRANSGENIC MURINE MODELS OF APML: A DEMONSTRATION OF THE
IMPORTANCE OF THE TARGETED COMPARTMENT |
The PML/RARA fusion gene, resulting from the t(15:17) balanced
reciprocal translocation characteristic of APML, is among the most
thoroughly studied of the leukemia-associated fusion
genes.13-17 Several transgenic models of APML have been
generated using an identical breakpoint 1-derived PML/RARA
cDNA14 expressed in different hematopoietic compartments
(Fig 1). Grisolano et al,18 in our laboratory, developed an
expression construct that directed human cathepsin G (hCG) transgene
expression exclusively to the promyelocyte compartment in hematopoietic
cells, and subsequently used this construct to direct PML/RARA
expression to the murine promyelocyte compartment in a C57BL/6 × C3H/He background.19 Despite a low level of PML/RARA
expression, 100% of transgene-expressing animals displayed altered
myeloid development, manifest by myeloid expansion in their bone marrow
and spleens and splenic extramedullary hematopoiesis, but normal
peripheral blood counts and myeloid differentiation. Over the course of
6 to 13 months, 30% of the transgenic animals from three different
founder lines developed AML. These leukemias were
characterized by profound leukocytosis, anemia and/or thrombocytopenia,
and extensive organ infiltration by leukemic cells with disruption of
normal histologic architecture. Morphologic differential analysis of
bone marrow and peripheral blood demonstrated markedly increased
numbers of promyelocytes, but full myeloid maturation was observed.
Transplantation of leukemia cells into SCID recipients resulted in
fatal leukemias in 100% of the recipients within 5 weeks. Treatment of
leukemic splenocytes in vitro with ATRA (106 mol/L)
resulted in nuclear changes that were morphologically consistent with
apoptosis, but these cells exhibited no morphologic or flow cytometric
evidence of differentiation. He et al20 reported similar
results using a nearly identical hCG-PML/RARA targeting construct in a
C57BL/6 × CBACa background. Evidence of myeloid expansion in the bone
marrow, spleen, lymph nodes, and thymus, but not peripheral blood, was
observed in 100% of transgenic animals by 12 months of age. Between 12 and 14 months, 10% of animals developed overt acute leukemia
characterized by peripheral leukocytosis, organ infiltration, and an
accumulation of blasts and promyelocytes in bone marrow and peripheral
blood. Furthermore, in agreement with the findings of Grisolano et al,
terminal myeloid maturation was shown.
Brown et al22 used a human MRP8 expression cassette to
direct expression of a PML/RARA cDNA to the myeloid lineage in an inbred FVB/N background. The MRP8 gene, which encodes an intracellular calcium-binding protein, is expressed in early myeloid and monocytic cells and throughout myeloid differentiation, based on coexpression with GR-1 and Mac-1 differentiation markers. The precise stage of
myeloid development at which MRP8 expression is activated has not been
clearly defined, although expression during embryonic development has
been detected in whole embryo suspensions as early as day E11, and
abundant MRP8-expressing myeloid cells were observed in fetal liver at
day E14. Low levels of MRP8 expression have also been observed in
nonhematopoietic tissues including lung, spinal cord, muscle, and
thymus; expression in the skin was originally not reported (see
below).23,24 PML/RARA expression in transgenic animals was
detected by Western blotting in bone marrow and peripheral blood in 8 of 9 founder lines, and a diffuse pattern of PML/RARA distribution was
demonstrated by immunofluorescence staining in the granulocytic series.
Subtle decreases in cell surface GR-1 expression, a marker of myeloid
differentiation, and decreased neutrophil granularity were evident by
fluorescence-activated cell sorter (FACS) analysis, but normal
hematopoietic cell numbers and morphologic differentiation were
observed in bone marrow and peripheral blood. Assessment of the latency
and incidence of leukemias was complicated by a retinoid-responsive
epidermal papillomatosis syndrome which developed in the highest
expressing lines. Acute myeloid leukemias developed in 12 animals from
five different founders (5% of surviving mice at the time of
publication). Leukemias were characterized by an accumulation of large
numbers of myeloperoxidase-positive promyelocytes with prominent
azurophilic granules. However, unlike the observations of Grisolano et
al and He et al, no evidence of granulocytic maturation was seen in the
leukemic animals. Treatment of leukemia cells with ATRA in vitro led to
morphologic and flow cytometric evidence of differentiation; treatment
of a limited number of leukemic animals with ATRA in vivo led to
variable results, although at least one animal appeared to enter a
complete remission. Transplantation of leukemic versus preleukemic bone
marrow cells from transgenic animals into irradiated recipients led to
100% versus 13% incidences of leukemia, respectively.
Early et al25 used CD11b regulatory sequences to direct
expression of a PML/RARA cDNA to a more differentiated granulocytic compartment in transgenic mice in an ICR Swiss or non-Swiss background. In this regulatory context, no leukemias were
observed, despite demonstration of PML/RARA expression in bone marrow
by reverse transcriptase-polymerase chain reaction (RT-PCR) assays. The
only apparent abnormality in these animals was a decrease in myeloid progenitors and a prolonged period of bone marrow suppression after
sublethal irradiation, suggesting a subtle defect in myelopoiesis.
Finally, Greer et al attempted to direct PML/RARA expression to the
murine hematopoietic stem cell compartment by inserting a PML/RARA cDNA
(linked to an internal ribosomal entry site) into the second coding
exon of a c-fes gene targeting construct (cited in 26). No
leukemias were observed in these studies. Transgene mRNA expression was
detected in bone marrow using RT-PCR, but protein expression within the
hematopoietic compartment was not clearly detected. As such, the
significance of these results is unclear (Peter Greer, personal
communication, July 1998).
He et al21 also targeted the expression of PLZF/RARA, a
variant APML-associated fusion cDNA, to the promyelocyte
compartment using the same hCG targeting construct in a C57BL/6 × B6CBACa background. Similar to the PML/RARA-CG mice, 100% of these
animals developed a myeloproliferative preleukemic state. Acute
leukemias subsequently developed following a similar 6- to 18-month
latency period; unlike the PML/RARA mice, however, the penetrance of
the leukemia phenotype was also 100%. These mice appeared to have a
less pronounced differentiation block than was observed in the PML/RARA-CG mice, with a decreased percentage of blasts and
promyelocytes, and a higher percentage of terminally differentiated
myeloid cells in the bone marrow and peripheral blood. Finally,
treatment of PLZF/RARA leukemic animals with ATRA resulted in a minimal
response, compared with transient complete responses observed in their
PML/RARA animals. The potential effects of random integration on
transgene expression patterns and/or transgene dose cannot be formally
excluded as contributing the differences between PML/RARA- and
PLZF/RARA-expressing animals. The analysis of multiple founder lines
and semi-quantitative analysis of transgene expression levels, however,
suggests that differences among individual leukemia-associated fusion
genes can, in fact, contribute to the different leukemia phenotypes in
the same cellular compartment.
| |
SEED VERSUS SOIL: FUTURE DIRECTIONS IN MURINE LEUKEMIA MODELS |
From the composite analysis of these studies, it is clear that both the
PML/RARA and PLZF/RARA fusion genes are leukemogenic when expressed in
the appropriate developmental context. The prolonged latency and
variable penetrance of the leukemia phenotype suggest that both
PML/RARA and PLZF/RARA expression can cause APML, but neither is
sufficient to do so. However, the precise role of the hematopoietic
developmental context of PML/RARA expression in the generation of
leukemia remains incompletely defined. The importance of the cellular
"soil" is emphasized by the failure of PML/RARA to cause
leukemias when expressed late in myeloid differentiation (under control
of the CD11b promotor), and by differences in the phenotypes resulting
from CG- and MRP8-directed PML/RARA expression. For example, despite an
accumulation of immature myeloid cells, terminal differentiation was
observed in leukemias derived from the PML/RARA-CG mice, but not
PML/RARA-MRP8 mice. These differences in differentiation phenotype may
reflect the fact that CG expression is limited to the promyelocytic
compartment, whereas MRP8 expression begins at a similar point in
myeloid differentiation, but remains active throughout terminal
differentiation (Table 1). The fact that a
similar, but not identical, leukemia phenotype was observed when a
different APML-associated fusion gene (PLZF/RARA) was expressed in the
promyelocyte compartment highlights the contribution of the individual
leukemia-associated cDNA (the "seed") for the determination of
the leukemia phenotype. As discussed above, however, the potential effects of random integration on transgene expression pattern and/or
"dose" cannot be dismissed as a potential explanation for the
difference in leukemia phenotype or penetrance between the PML/RARA and
PLZF/RARA lines. Moreover, the potential role of mouse strain
differences contributing to the different observed phenotypes cannot be
formally excluded at this time.
It is not known what effect PML/RARA expression would exert at an
earlier stage of myeloid development, or in a different hematopoietic
lineage. One possibility is that the intracellular regulatory milieu of
the compartment in which PML/RARA is expressed determines the
phenotypic characteristics of the resultant leukemia. In this scenario,
targeting PML/RARA expression to a more primitive myeloid compartment
might cause a less differentiated leukemia phenotype, whereas
expression in the erythroid or megakaryocytic compartments might result
in the generation of acute leukemias with phenotypic features of those
lineages. Conversely, targeting the expression of a different fusion
gene characteristically associated with a less differentiated leukemia
phenotype (such as an AML/ETO cDNA) to the promyelocyte compartment
under the control of CG regulatory sequences might, in turn, cause a
promyelocytic leukemia phenotype. Another possibility is that PML/RARA
itself may direct an APML phenotype exclusively, regardless of the
hematopoietic cell type in which it is expressed. Alternative outcomes
of targeting PML/RARA expression to other hematopoietic compartments
include (1) a failure to cause leukemias, if the myeloid precursor
stage at which CG and MRP8 expression is activated represents the
earliest hematopoietic compartment sensitive to transformation by
PML/RARA; or (2) embryonic lethality, if expression in other
compartments disrupts normal hematopoiesis, as seen in the
case of the AML/ETO and CBF/MYH11 knock-in experiments.
To definitively address the role of the target cell "soil" in a
murine model of PML/RARA-mediated leukemogenesis, PML/RARA expression
must be targeted to discrete hematopoietic developmental compartments.
A critical component in the design and ultimate interpretation of these
experiments will be the choice of loci whose expression patterns are
well characterized and limited to hematopoietic cells, such as those of
developmentally regulated hematopoietic growth factor receptors. As
discussed above, the targeted knock-in transgenesis approach (Fig 2)
should prove to be ideally suited for this purpose, since it eliminates
the potential variables of gene dosage and locus-specific effects on
transgene expression due to random integration, and allows valid
comparison of the phenotypes arising from the expression of different
fusion genes from the same locus. We anticipate that over the next few years, the application of these recent technological advances in the
generation of gain-of-function transgenic models will enable investigators to elucidate the potentially important role of the target
cell in leukemic transformation.
| |
FOOTNOTES |
Submitted September 29, 1998; accepted November 23, 1998.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Timothy J. Ley, MD, Washington University
School of Medicine, Division of Bone Marrow Transplantation and Stem
Cell Biology, 660 S Euclid Ave, Campus Box 8007, St Louis, MO
63110-1093; e-mail: timley{at}im.wustl.edu.
| |
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INTRODUCTION
WHAT IS THE TRANSFORMED...