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REVIEW ARTICLE
From the Department of Biochemistry, St Jude
Children's Research Hospital, Memphis, TN; and the Department of
Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical
School, Boston, MA.
In 1957, Charlotte Friend described a novel
retroviral disease in mice characterized by splenic enlargement,
erythroleukemia, and death.1 This rapidly progressive
disease, now known as Friend disease, has provided a powerful tool for
the study of multistage carcinogenesis. Transformed murine
erythroleukemia (MEL) cells, isolated from Friend virus-infected mice,
have also provided a versatile model system for the study of
erythroblast differentiation and erythropoietin (Epo)-induced signal
transduction in vitro. Over the years, Friend disease has provided
major insights into the molecular evolution of leukemia, the normal
mechanisms of Epo receptor (EpoR) activation and, most recently, the
molecular mechanisms of leukemia resistance. In this review, we
summarize the molecular insights gained from the study of Friend
disease. We focus on recent advances, with a special emphasis on
studies of the Friend virus susceptibility locus,
Fv2. 2 Following inoculation of a susceptible mouse with Friend virus
complex, Friend disease evolves in 2 stages.3,4 In the first stage, the mouse develops massive splenic enlargement due to the
polyclonal proliferation of splenic erythroblasts. These erythroblasts
are not frankly transformed, however, and their transfer to another
animal does not result in tumors.5 The primary mitogenic
event underlying this polyclonal expansion is constitutive activation
of the EpoR.4,6 During this early stage of disease, there
is a marked expansion of erythroid progenitor cells (burst-forming
units-erythroid [BFU-E] and colony-forming units-erythroid
[CFU-E]).7,8
The second stage of Friend disease is marked by the emergence of fully
transformed cells in the spleen and, eventually, the blood, bone
marrow, and liver.5 These transformed cells form spleen
colonies in genetically anemic Sl/Sld
mice, are tumorigenic in vivo, and give rise to stable cell lines in
vitro.5,9,10 Mice infected with the polycythemia-inducing strain of Friend virus (see below) often die during the first stage of
disease because of splenic rupture. Mice that survive the first stage,
however, will develop leukemia.11 Most emerging leukemic
clones either fail to express p53, or they express a mutant form of p53
that is inactive, demonstrating that loss of p53 function is a common
event in disease progression.12-14 In addition, an
ets family transcriptional activator, Sfpi1/PU.1 (spleen
focus-forming virus [SFFV] proviral integration 1), is activated in
70% to 95% of Friend virus-induced
erythroleukemias.15,16 The high incidence of p53
inactivation and Sfpi1/PU.1 activation suggests that these events are
critical to the evolution of erythroleukemia. Isolated MEL cells have
the characteristic appearance of immature erythroblasts. These cells
remain transformed and Epo-independent and demonstrate constitutive
activation of the EpoR.17 Molecular events underlying the
first and second stages of Friend disease have been
reviewed.4,18,19
Friend virus complex consists of 2 viruses, a replication-competent
Friend helper virus (F-MuLV) and a replication-defective SFFV. There
are at least 2 naturally occurring variants of SFFV, called
SFFVP (polycythemia strain) and SFFVA (anemia
strain). Mice infected with the viral complex of SFFVP and
F-MuLV (also known as FVP) become polycythemic, while mice infected
with SFFVA and F-MuLV (FVA) develop anemia as a result of
volume expansion.20 In contrast to other acutely oncogenic
retroviruses, SFFV does not carry a constitutively active, mutant form
of a host gene. Instead, SFFV encodes a truncated form of a retroviral
envelope protein, gp55, which can bind and activate the
EpoR.6,21 Indeed, virally encoded gp55 can replace Epo in
supporting the formation of erythroid colonies in vitro, but only in
the presence of the EpoR.22
The polycythemia- and anemia-inducing strains of Friend virus exhibit
differential transforming effects in vitro.23 Both SFFVP and SFFVA induce BFU-E in methylcellulose
in the absence of exogenous Epo. However, in contrast to
SFFVP, SFFVA-induced bursts require Epo to
undergo terminal differentiation. FVA-infected erythroblasts
proliferate in vivo despite low levels of endogenous Epo.24 Withdrawal of Epo from FVA-infected erythroblasts
at the CFU-E stage results in rapid commitment to undergo
apoptosis.24 Thus, while FVA-infected erythroblasts can
proliferate in the absence of Epo, Epo is required for their survival
and terminal differentiation. Erythroblasts isolated from the spleens
of FVA-infected mice (FVA cells) provide an excellent model system for
the study of Epo-dependent terminal differentiation in
vitro.25
Early evidence from several investigators, including Hankins,
Ruscetti, and Kabat, demonstrated that SFFV is the causative agent in
the first stage of Friend disease. In fact, the gp55 oncoprotein alone
was shown to induce BFU-E in vitro.26 Moreover, gp55P (from SFFVP) supports the growth of
Epo-dependent cell lines in vitro, suggesting that gp55P
might activate the cell surface EpoR directly.27
The next clue to the function of the gp55 envelope arose from the
cloning of the EpoR itself. The murine EpoR was expression-cloned from
Epo-independent MEL cells expressing cell surface Epo-binding proteins.28 The EpoR polypeptide was shown to be the first
member of the cytokine receptor superfamily, which includes the
receptors for interleukin (IL)-2, IL-3, granulocyte-macrophage
colony-stimulating factor, and several other hematopoietic
cytokines.29,30 Initially, the EpoR was heterologously
expressed in an IL-3-dependent, pro-B lymphocyte line, Ba/F3.
Ba/F3-EpoR cells could be grown in either Epo or IL-3, demonstrating
that the EpoR activates the appropriate signal transduction pathways in
these cells. Next, Ba/F3-EpoR cells were infected with a retrovirus
encoding gp55P. The EpoR and gp55P were
shown to form a physical and functional complex in these cells,
resulting in their transformation to growth factor independence.
Expression of gp55 in parental Ba/F3 cells, in the absence of the EpoR,
failed to transform the cells, demonstrating that both proteins are
required for Epo-independent growth.6
The nature of the molecular interaction between gp55P and
the EpoR is now understood in considerable detail. Gp55P
binds to the EpoR both at the cell surface31 and within
the endoplasmic reticulum32 of Friend virus-infected
erythroblasts. Binding of gp55P results in the
stabilization and constitutive activation of the EpoR.32
Gp55P selectively activates the murine EpoR but not the
human EpoR, despite the high (92%) amino acid identity between these
polypeptides.33,34 Gp55P does not activate
other members of the cytokine receptor superfamily. The critical
contact between gp55P and the murine EpoR occurs within the
transmembrane region of these cell surface proteins,35-37
and a productive interaction between the EpoR and gp55P
occurs when both proteins are expressed at the cell
surface.35,37-39 The gp55P-EpoR interaction
cannot be transmitted by cell-to-cell contact or by the administration of soluble gp55P to EpoR-expressing cells (A.D.,
unpublished observations, September 1999).
The gp55 envelope proteins of SFFVA and SFFVP
differ in a small number of amino acid residues, primarily in the
transmembrane region, and these differences appear to account for the
phenotypic variation of the disease.35,36,40
Gp55A does not support the growth of Epo-dependent cell
lines, which raises the question of whether it functionally interacts
with the EpoR. Gp55 from Rauscher leukemia virus (R-gp55; which is
closely related to gp55A) physically associates with the
EpoR.34 However, R-gp55 does not detectably interact with
the EpoR at the cell surface.41 Part of the explanation
for these differences may be that gp55A and R-gp55, when
compared with gp55P, are expressed at low levels on the
cell surface.42 Recently, it was shown that
gp55A induces the formation of CFU-E from fetal liver cells
without exogenous Epo.22 Neither gp55A nor
gp55P were able to induce CFU-E formation from fetal liver
cells that lacked the EpoR. Thus, the EpoR is required for
gp55A-induced erythroid colony formation. Whether this
reflects a requirement for a direct interaction between
gp55A and the EpoR remains to be determined.
The specific interaction between gp55P and the EpoR
underscores the importance of the EpoR in the evolution of
erythroleukemia. The EpoR can be constitutively activated by other
molecular mechanisms, also resulting in the development of
erythroleukemia. For instance, the EpoR can be activated by point
mutations34,43 or by erythroblast autocrine secretion of
Epo.44 Indeed, a constitutively active form of the EpoR
can result in induction of Friend-like disease.45 Other
molecular events resulting in up-regulation of EpoR activity, such as
insertional activation of EpoR expression,46,47 truncation of the EpoR carboxy terminus,48,49 or cellular loss of the negative regulatory phosphatase, Shp-1,50-53 may also
contribute to the evolution of erythroleukemia.
Although the EpoR polypeptide has been molecular
cloned,28 there are still questions about the structure
and composition of the cell surface EpoR complex. Several studies
indicate that the EpoR is a simple monomeric cytokine receptor capable
of homodimerization in response to Epo binding. A soluble secreted form
of the EpoR is sufficient for high-affinity Epo binding, supporting a
model of a single receptor subunit.54 The crystal
structure confirms the homodimeric structure of the Epo-bound,
activated EpoR.55,56 Additional studies suggest a more
complex membrane-bound EpoR conformation.57,58 Small
synthetic peptides are capable of activating EpoR dimerization,
providing a possible avenue for Epo-mimetic drug
design.59,60
Other studies suggest that the native cell surface EpoR complex may
contain additional subunits or accessory proteins. First, the EpoR
displays at least 2 different affinities for Epo, raising the
possibility of distinct receptor classes.61,62 Second, cross-linking studies with 125I-Epo reveal multiple classes
of cell surface EpoR, suggesting the presence of additional receptor
subunits.31,63-65 In one study, the EpoR was cross-linked
to a cell surface tyrosine kinase protein.66 In addition,
the EpoR interacts with a cytoplasmic tyrosine kinase, Jak2.67 Third, forced expression of the EpoR complementary
DNA in some lymphoid cell lines, such as CTLL68,69 and
HT-2,70 confers Epo binding but not Epo-induced
mitogenesis. These cells lack a required factor in the trans-acting
environment.70 One study suggests that the Kit receptor
tyrosine kinase activates the EpoR directly, thereby accounting for the
synergistic activities of Epo and Kit ligand (Mgf), also known as SCF,
in erythropoiesis.71 Emerging data discussed below suggest
that a truncated form of the Stk receptor tyrosine kinase, encoded by
the Fv2 Friend virus susceptibility locus, may also function
as a subunit of the EpoR complex.2
A number of host genes have been identified that affect the
susceptibility of mice to Friend virus-induced erythroleukemia (Table
1). These genes can be divided into
several categories based on their proposed mechanism of
resistance.72 The first group consists of genes that
dominantly interfere with the infection of target cells by the
retrovirus. Fv4 encodes a protein related to the MuLV Env
protein, which blocks ecotropic retroviral receptors.73 Fv1 encodes a Gag-related protein, which interferes with the
retroviral life cycle.74 The second group consists of
genes that alter the immune response to Friend virus infection.
Fv3 affects the susceptibility of mice to Friend
virus-induced immunosuppression.75 Two
H2-linked loci, Rfv1 and Rfv2, and one
non-H2-linked locus, Rfv3, affect the recovery
from Friend virus infection.76 The third group consists of
genes that affect the potential of infected target cells to proliferate
and differentiate. Fv5 determines whether FVP will cause
anemia or polycythemia in certain strains of mice.77
Mutations in Kit and Mgf either diminish the
number of available target cells or their potential to
proliferate.78,79 These genes are required for normal
erythropoiesis, emphasizing the importance of pre-existing
erythropoietic pathways for the development of Friend disease.
Fv2 is another host factor that affects the proliferation of SFFV-infected erythroblasts.80 Susceptibility at the Fv2 locus, which is dominant, is present in most inbred strains of mice. The exception is C57BL/6 and related strains, which are Fv2-resistant (Fv2rr). Fv2 does not interfere with retroviral entry into cells or the retroviral life cycle.81 Instead, Fv2 determines the potential of SFFV-infected erythroblasts to proliferate in response to gp55. Fv2 acts in a cell autonomous manner.82 Indirect evidence suggests that Fv2 and gp55 are functionally interrelated. Fv2-mediated resistance can be circumvented by deletions within the ecotropic domain of gp55, but the same mutants are less active than wild-type gp55 in Fv2-sensitive (Fv2ss) mice.83
Recently it has been shown that Fv2 is Ron, a member of the Met subfamily of receptor tyrosine kinases.2 Ron encodes the Stk receptor tyrosine kinase, and a naturally expressed truncated form of Stk (SF-Stk) confers susceptibility to Friend virus-induced erythroleukemia. The evidence can be summarized as follows. First, the expression of SF-Stk correlates with susceptibility to Friend disease. SF-Stk is the major expressed form of Stk in Fv2ss erythroid cells; however, SF-Stk is expressed at very low levels or is absent in Fv2rr erythroid cells. The 5' end of the SF-Stk transcript has been mapped to intron 10 of Ron.84 The presumptive basis for the difference in expression is a 3-nucleotide deletion in C57BL/6 DNA, which mutates a GATA binding site and causes a 6-fold difference in promoter activity. Second, targeted disruption of Stk in Fv2ss mice causes resistance to Friend disease. Third, enforced expression of SF-Stk in Fv2rr mice confers susceptibility to Friend disease. These data strongly suggest that SF-Stk confers susceptibility to gp55-mediated erythroblastosis and that C57BL/6 mice are resistant because they fail to express the protein. The molecular mechanism by which SF-Stk confers susceptibility to Friend disease is not known. Possibly, full-length Stk would have the same effect as SF-Stk if expressed at an equivalent level. Alternatively, there may a unique requirement for SF-Stk. The predicted protein encoded by the SF-Stk transcripts lacks the extracellular domain of Stk but retains the transmembrane and kinase domains.84 By analogy to other receptor tyrosine kinases, loss of the extracellular domain may contribute to constitutive activation.85 SF-Stk is closely related to the avian oncogene v-sea, which causes erythroblastosis and anemia in chickens.86 The v-sea oncogene is a transmembrane protein, which has an extracellular domain related to an avian retroviral envelope and an intracellular domain derived from c-sea. One possible mechanism is that gp55 and SF-Stk together form the functional equivalent of v-sea. Crosstalk could occur between gp55, SF-Stk, and components of the EpoR complex (eg, Jak2), resulting in activation of downstream signaling cascades. In support of this model, SF-Stk and the EpoR have been shown to physically interact in COS cells.87 Based on differences in molecular weight, Stk does not appear to be one of the proteins previously identified by 125I-Epo cross-linking to the EpoR.31,63-65 A second possibility is that SF-Stk functions independently of the gp55-EpoR complex to enhance erythroid cell survival or proliferation. The lack of an erythroid defect in (Fv2rr)
C57BL/6 mice suggests that SF-Stk does not have a role in normal
erythropoiesis. Still, the role of full-length Stk remains to be
determined. Stk is the receptor for macrophage-stimulating protein
(also known as hepatocyte growth factor-like protein or
Hgfl).88 Targeted disruption of the first exon of
Stk in mice causes increased nitric oxide production from
peritoneal macrophages in response to interferon- The Met subfamily of receptor tyrosine kinases includes Met, Ron, Stk
(the murine homolog of Ron), and v-sea. These receptors have
a distinctive 2-tyrosine docking site in the C-terminal tail that
mediates interactions with multiple SH2-containing signal transducers.91 Ligand binding elicits a complex biologic
response that includes cell growth, dissociation, motility, and
polarization.92 Recent evidence suggests that the Met
subfamily may function as second subunits or coreceptors for the
cytokine receptor family. Stk has been shown to colocalize with and
activate the IL-3 receptor common Based on the likely physical and functional interaction between the EpoR and Stk,87 several questions emerge. For instance, it will be interesting to determine (1) whether activation of the EpoR results in activation of Stk kinase activity or phosphorylation of the multifunctional docking site; (2) whether activation of Stk by Hgfl results in EpoR phosphorylation or activation of Jak2; (3) whether EpoR and Stk can be cross-linked at the cell surface or whether previously identified Epo/EpoR cross-linked complexes62 contain Stk; and (4) whether specific activation or phosphorylation events correlate with the progression of Friend disease.
The molecular events underlying the first and second stages
of Friend disease are now understood in considerable detail (Figure 1). In the first stage of Friend disease,
constitutive activation of the EpoR by gp55 causes uncontrolled,
polyclonal proliferation of infected erythroblasts (Figure 1A).
Susceptibility to gp55-induced erythroblastosis depends on expression
of SF-Stk. Recent studies suggest that the mechanism may involve a
direct interaction between the EpoR and SF-Stk.87 In the
second stage of Friend disease, activation of Sfpi1/PU.1 and loss of
p53 contribute to erythroleukemic transformation (Figure 1B and Table
2). The transformation-specific targets
of Sfpi1/PU.1 are not known, although one potentially relevant target
is Fli1.95 Another potential target is SF-Stk. SF-Stk
expression is down-regulated during terminal differentiation of
FVA-infected, primary erythroblasts (P.N., unpublished
observations, December 1998). Potentially, Sfpi1/PU.1 could
activate SF-Stk through Ets sites in the SF-Stk promoter.2
Constitutive SF-Stk expression, in turn, could contribute to the
immortalization of infected erythroblasts. Consistent with this idea,
SF-Stk is highly expressed in MEL cells but not most other
hematopoietic cell lines. Further, enforced expression of
full-length Stk causes ligand-dependent apoptosis of MEL cells but
not Ba/F3 cells, indicating that Stk signaling has a direct effect on
MEL cell survival.96
It is interesting to contrast the progression of FVP-induced disease with that of F-MuLV, which is gp55-independent. F-MuLV-induced erythroleukemia has a longer latency (6 weeks) than FVP-induced disease (1-2 weeks), is oligoclonal rather than polyclonal and is associated with the activation of Fli1 rather than Sfpi1/PU.1 expression.97-99 Most MEL cell lines derived from Fli1-expressing primary erythroid tumors are Epo-dependent. However, with additional passages in vivo Epo-independent MEL lines are obtained, which show a high frequency of genomic rearrangements in Epo and autonomous Epo expression.100 Thus, whether it occurs early in the course of disease (FVP) or late (F-MuLV), deregulation of EpoR signaling appears to be a common step in the progression of Friend virus-induced erythroleukemia.
In summary, Friend virus-induced erythroleukemia has provided a model system for the molecular understanding of the multistage nature of leukemogenesis. Critical elements of the disease involve the interaction of host gene products (EpoR, Sfpi1/PU.1, and SF-Stk) and retroviral gene products (gp55P or gp55A). The recent demonstration of a specific role of the cell surface tyrosine kinase SF-Stk in the process of leukemogenesis underscores the importance of multiple signal transduction pathways in normal hematopoiesis and leukemogenesis. Stk is a member of a large family of cell surface tyrosine kinase receptors, while the EpoR is a member of a large family of cytokine receptors. Accordingly, it will be interesting to determine whether other transmembrane tyrosine kinases and cytokine receptors interact at the cell surface of hematopoietic cells. These tyrosine kinases may have a more general role as modifiers (coreceptors) of cytokine receptor signaling. In this regard, it is interesting that Kit encodes a receptor tyrosine kinase that is essential for normal erythropoiesis. Mgf and Epo are potent comitogens for early erythroid progenitor cells, and this effect may be due to direct interaction between Kit and the EpoR.71 Finally, identification of SF-Stk as the product of the Fv2 gene provides general insights into the mechanism of cancer resistance in mice and perhaps in humans. Friend disease develops when the proliferation of infected erythroblasts outpaces the ability of the host immune system to suppress the infection.76 Mice that are deficient in SF-Stk, such as the C57BL/6 strain, have lost little or none of their normal erythropoietic response; however, gp55-mediated erythroid proliferation is slowed. As a result, they gain resistance to Friend virus-induced erythroleukemia.
We thank James Ihle, Dwayne Barber, and Maurice Bondurant for helpful discussions and advice on the manuscript.
Submitted February 28, 2000; accepted June 6, 2000.
Supported by National Institutes of Health (NIH) grant RO1 CA84214 (P.A.N.), NIH Cancer Center Support Grant P30 CA21765, and the American Lebanese Syrian Associated Charities.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Alan D. D'Andrea, Dana-Farber Cancer Institute, Department of Pediatric Oncology, Harvard Medical School, 44 Binney St, Boston, MA 02115; e-mail: alan_dandrea{at}dfci.harvard.edu.
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Introduction
Multistage Friend disease
.
-chain, another member of the
cytokine receptor family.