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Previous Article | Next Article 
Molecular and Cellular Biology, January 2000, p. 628-633, Vol. 20, No. 2
Departments of Biochemistry and Molecular
Biophysics,1
Microbiology,2 and
Pathology3 and Howard Hughes
Medical Institute,4 Columbia University College
of Physicians and Surgeons, New York, New York 10032
Received 6 April 1999/Returned for modification 28 April
1999/Accepted 15 October 1999
Abelson murine leukemia virus (A-MuLV) is an acute transforming
retrovirus that preferentially transforms early B-lineage cells both in
vivo and in vitro. Its transforming protein, v-Abl, is a tyrosine
kinase related to v-Src but containing an extended C-terminal domain.
Many mutations affecting the C-terminal portion of the molecule block
the pre-B-transforming activity of v-Abl without affecting the
fibroblast-transforming ability. In this study we have determined the
abilities of both wild-type and C-terminally truncated (p90) forms of
v-Abl to transform cells from p53 Abelson murine leukemia virus
(A-MuLV) is an acutely transforming retrovirus which causes pro-B or
pre-B tumors in infected animals (9). In vitro, A-MuLV
transforms early B cells, cells from other hematopoietic lineages, and
a permissive subset of 3T3 fibroblasts (the P-3T3 subline)
(34). p160 v-Abl, the oncoprotein encoded by A-MuLV,
exhibits constitutive protein tyrosine kinase activity (35).
A C-terminally truncated mutant of p160, p90 v-Abl, is defective for
early B-cell transformation but retains the ability to transform P-3T3
cells (26, 35). The phenotype of this virus led to the
suggestion that the C terminus of v-Abl is important for the pre-B-cell
preference of A-MuLV.
Despite the presence of a strongly transforming oncogene,
A-MuLV-induced lymphomas are usually clonal or oligoclonal, suggesting that other events in addition to expression of v-Abl are required for
tumor formation (12). Furthermore, in some cells where v-Abl does not cause transformation, it has been shown to cause growth arrest
or apoptosis (31, 47). These facts suggest that tumor suppressors, such as p53, might play an important role in determining whether v-Abl expression leads to transformation or apoptosis and might
be important for the striking early B-cell preference shown by A-MuLV
in vivo.
p53 is a potent tumor suppressor which is mutated in more than half of
all human tumors (21). Mice with p53 gene deletions develop
normally but are highly prone to tumor development (8, 17).
Indeed, p53 is not required for normal cell growth but acts to prevent
proliferation under circumstances of cellular stress. Hence, the
normally low levels of p53 increase following DNA damage, certain
oncogenic insults, hypoxia, and a variety of other cellular stresses
(19). Activation of p53 prevents cell proliferation by
inducing either cell cycle arrest or apoptosis. p53 is a
sequence-specific DNA binding protein that activates transcription of
genes involved in cell cycle arrest and in apoptosis, like the
cyclin-dependent kinase inhibitor p21 (19).
Recent data from other laboratories provide evidence that p53 may play
a role in v-Abl transformation. More than 40% of early B-cell lines
resulting from A-MuLV transformation of bone marrow cells (BMCs) in
vitro develop p53 mutations (43). The susceptibility of the
permissive subline of 3T3 cells to transformation by A-MuLV correlates
with a failure to induce a p53 response to DNA damage in these cells
(16). These considerations led us to study the ability of
wild-type and mutant forms of v-Abl to transform bone marrow cells from
p53 Cells and mice.
A-MuLV-transformed bone marrow cells and
tumor cells derived from A-MuLV-infected mice were maintained in RPMI
1640 medium supplemented to contain 10% heat-inactivated fetal calf
serum and 50 µM 2-mercaptoethanol. Tumorigenicity studies were
conducted with p53 mutant mice. The p53 mutant mice were obtained from
The Jackson Laboratory; they are derived from 129/SV ES cells and in a
129/SV × C57BL/6 mixed genetic background (17).
A-MuLV preparation and bone marrow transformation assay.
P160 and P90A A-MuLV virus stocks were prepared by rescuing virus from
transformed nonproducer NIH 3T3 cells with Moloney MuLV (M-MuLV) helper
virus (10, 35). The titers of the transforming virus in the
stocks were determined after infection of NIH 3T3 cells
(36). Primary BMCs were recovered from the femurs of 4- to
6-week-old p53 mice. The bone marrow transformation assay was performed
as described elsewhere (15, 33).
In vivo tumorigenicity study.
Offspring from heterozygote
crosses were obtained so that wild-type (p53+/+),
heterozygote (p53+/ FACS analysis.
Preparation, staining, and analysis of cells
were performed as described previously (18). All antibodies
used were obtained from Pharmingen Inc. (San Diego, Calif.). The FACS
analysis was performed on cytometers from Becton Dickinson. The results
were analyzed by using CellQuest software (Becton Dickinson).
Western and Southern blotting.
Whole-cell extracts were
prepared from primary or cultured cells as described elsewhere
(46); equal amounts of cellular proteins were separated by
sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE).
v-Abl proteins were detected by using rabbit anti-Abl antibody (C-19;
Santa Cruz Biotechnology) with the standard protocol.
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
p53 Deficiency Increases Transformation by v-Abl
and Rescues the Ability of a C-Terminally Truncated v-Abl Mutant To
Induce Pre-B Lymphoma In Vivo
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
/ mice. Lack of p53
increases the susceptibility of bone marrow cells to transformation by
v-Abl by a factor of more than 7 but does not alter v-Abl's preference
for B220+ IgM pre-B cells. p53-deficient mice
have earlier tumor onset, more rapid tumor progression, and decreased
survival time following A-MuLV infection, but all of the tumors are
pre-B lymphomas. Thus, p53-dependent pathways inhibit v-Abl
transformation but play no role in conferring preferential
transformation of pre-B cells. Surprisingly, the C-terminally truncated
form of v-Abl (p90) transforms pre-B cells very efficiently in mice
lacking p53, thus demonstrating that the C terminus of v-Abl does not
determine preB tropism but is necessary to overcome p53-dependent
inhibition of transformation.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
/ mice in vivo and in vitro. The results show that
BMCs lacking p53 are transformed more efficiently by v-Abl and that the
latency period for v-Abl-dependent tumor formation in vivo is reduced in mice lacking p53. Our data also show that neither the status of the
p53 gene nor the C-terminal portion of v-Abl is responsible for the
early B-cell tropism of A-MuLV.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
), and null (p53/)
littermates could be compared. The mice were genotyped by PCR 3 weeks
after birth. Neonatal mice (48 h or less postpartum) were injected
intraperitoneally with 5 × 104 focus-forming units
(FFU) of A-MuLV-P160 or A-MuLV-P90A. Infected mice were monitored
regularly for the development of symptoms of Abelson disease. Afflicted
mice were sacrificed by CO2 asphyxiation when the disease
became near terminal. Diagnosis of disease was based on gross
pathological examination, histochemical staining, and
fluorescence-activated cell sorting (FACS) analyses.
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RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
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p53-deficient mice have earlier onset, more rapid tumor
progression, and decreased survival time following infection with
A-MuLV-P160.
To evaluate whether the development of Abelson
disease was affected by the absence of p53, mating pairs of mice
heterozygous for the p53 null mutation were crossed to generate
p53+/+, p53+/, and p53/
littermates. Neonatal mice derived from these crosses were injected intraperitoneally with 5 × 104 FFU of A-MuLV within
48 h of birth. Infected mice were monitored regularly for the
appearance of disease symptoms. Animals were killed and autopsied when
signs of disease were evident. Mortality curves (Fig.
1A) illustrate that wild-type mice had
the longest survival time, with the median tumor latent period being 49 days; p53 heterozygotes had a shorter survival time, with the median tumor latent period being 40.5 days. In comparison, p53 null mice had
the shortest survival time, the median tumor latent period being only
31 days and the tumor incidence reaching 100% by 40 days. The disease
seemed to progress more rapidly in p53/ mice. The
infected p53/ mice, if not sacrificed, usually died 1 or 2 days after symptoms were observed, compared to several days and up
to a week for wild-type mice. These data show that lack of p53
increases susceptibility of mice to transformation by v-Abl.
|
mice showed an intermediate phenotype with
respect to tumor formation. However, upon further analysis using a PCR assay, we found that two of four tumors from p53+/ mice
had lost the remaining wild-type allele. Using a functional assay based
on induction of p21 in response to gamma irradiation as described
previously (43), we found that one of two tumors which
retained a wild-type allele had lost p53 function as measured by
induction of p21. Thus, three of four tumors from the
p53+/ animals were functionally p53/. A
similar observation was made recently by Unnikrishnan et al. (44).
The target cell of A-MuLV-P160 is the same in wild-type and
p53-deficient mice.
In most cases, the gross pathology of the
disease was typical of A-MuLV lymphoma, regardless of p53 genotype.
Histochemical analyses of infected mice showed high-grade lymphoblastic
lymphomas that were morphologically and histologically
undistinguishable in p53/ and p53+/+ mice
(data not shown).
/ and
p53+/ mice have earlier disease onset, more rapid disease
progression, and shorter survival time, the surface markers on tumors
cells derived from these mice were the same as those from infected
wild-type mice. Surface marker analyses of tumor cells from
p53/ mice showed an early B-cell phenotype:
B220+ IgM CD43low (B-cell
markers), CD4 CD8 CD3 (T-cell
markers), and Mac-1 GR-1 (myeloid
lineage markers). Thus, while p53 deficiency increases the
susceptibility to transformation by v-Abl in vivo, there is no change
in the early B-cell tropism of A-MuLV. The results suggest that while
p53-dependent mechanisms inhibit transformation by A-MuLV, they are not
responsible for determining the pre-B cell preference of the virus.
Loss of p53 complements the A-MuLV-P90A mutant for transformation in vivo. A-MuLV-P90A lacks most of the C-terminal portion of v-Abl (Fig. 1C). It transforms early B cells poorly both in vitro and in vivo but retains the ability to transform P-3T3 cells efficiently. We wished to test how p53 affected the transforming ability and lineage preference of this mutant.
Neonatal mice derived from the crosses of p53 heterozygotes were injected intraperitoneally with 5 × 104 FFU of the A-MuLV-P90A within 48 h of birth. Infected mice were analyzed as described previously for A-MuLV-P160-infected mice. A-MuLV-P90A is indeed defective for tumor induction in wild-type mice. All of the wild-type mice injected with A-MuLV-p160 developed disease within 80 days (Fig. 1A), whereas only 38% (6 of 16) of the p53+/+ mice injected with A-MuLV-P90A developed disease during the 120-day observation period (Fig. 1B). However, all p53/ mice
injected with A-MuLV-P90A developed disease within 60 days. The median
tumor latent period for p53/ mice upon A-MuLV-P90A
infection was 37.5 days (Fig. 1B), close to the mean time of 31 days
for the p160 strain in these mice (Fig. 1A). Heterozygous mice also
developed disease with A-MuLV-P90A: 86% (18 of 21) of the infected
mice developed disease during the 120-day observation period, with a
mean latent period of 67 days (Fig. 1B). These results suggest that the
C-terminal region is required for efficient tumor induction in
wild-type mice but dispensable in p53-deficient mice.
We examined v-Abl expressed in tumors raised in p53-wild-type and
-deficient mice injected with A-MuLV-P90A to determine whether animal
passage resulted in recombination to restore the C terminus to p90
v-Abl. In previous studies, pre-B lymphomas formed from A-MuLV-P90 were
shown to be revertants to larger forms of v-Abl or to have undergone
further deletion (26). Western blots showed that the v-Abl
proteins in A-MuLV-P90A-induced tumors from p53/ mice
were all 90 kDa (Fig. 2A). In contrast,
as previously observed (26), p90 tumors from
p53+/+ mice contained either smaller or larger forms of
v-Abl (Fig. 2B). Two of them contained v-Abl protein of approximately
120 kDa; others contained v-Abl protein in the 70- to 80-kDa range. Some tumors contained both 90-kDa and smaller or larger forms of v-Abl;
we assume that this reflects tumor oligoclonality. Thus, absence of p53
increases transformation efficiency, decreases latency, and abrogates
recombination of A-MuLV-P90A.
|
/ mice.
A-MuLV-P90A targets the pre-B-cell in p53/
mice.
At autopsy, the gross pathology of the diseased
p53/ animals infected by A-MuLV-P90A was the same as
that for mice infected with A-MuLV-P160 and typical for Abelson
disease. When analyzed by FACS, the tumors showed an early B-cell
phenotype: B220+ IgM CD43low
CD3 CD4 CD8
Mac-1 or Mac-1low GR-1.
Mac-1low expression was observed in four of nine cases of
A-MuLV-P90A-induced tumors in p53/ mice; its
significance is unclear at this time. A PCR-based assay for DNA
rearrangement showed that these tumor cells all completed DH to JH rearrangement, suggesting they are
B-lineage cells (data not shown). Histochemical staining also confirmed
that A-MuLV-P90A induced pre-B lymphomas in p53-deficient mice (data
not shown). The results demonstrate that the C-terminal region of v-Abl
is not responsible for the pre-B-cell tropism of A-MuLV, since the C-terminal deletion mutant virus, A-MuLV-P90A, still exclusively transforms pre-B cells in p53/ mice.
Loss of p53 increases the efficiency of A-MuLV-dependent
transformation in vitro.
To determine whether the absence of an
intact p53 gene affects v-Abl-induced lymphoid transformation in vitro,
BMCs from p53/ mice and p53+/+ littermate
controls were infected with A-MuLV-P160 or A-MuLV-P90A and then
cultured in soft agar. Transformed colonies were counted after 14 days.
A-MuLV-P160 induced colony formation in both p53+/+ and
p53/ BMCs, but it induced sevenfold more colonies in
p53/ BMCs (Table 1). In
comparison, A-MuLV-P90A did not induce colony formation in either
p53+/+ or p53/ BMCs (Table 1), even though
A-MuLV-P90A could induce pre-B lymphomas in p53/ mice
with good efficiency. A similar discrepancy between in vivo and in
vitro transformation was observed previously with some smaller
variants of A-MuLV-P90, which are highly oncogenic in vivo but do not
transform BMCs in vitro at high efficiency (26).
|
/ BMCs. The four p53+/+ and twelve
p53/ lines were B220+ IgM
CD43low and negative for other lineage markers. Thus, lack
of p53 increases the susceptibility of bone marrow cells to
transformation by wild-type v-Abl, but it does not alter A-MuLV's
preference for B220+ IgM pre-B cells as
targets in vitro.
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DISCUSSION |
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|
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
|---|
In this study we have determined the ability of A-MuLV-P160 and
A-MuLV-P90A to transform BMCs from p53/ mice both in
vitro and in vivo. Our data lead to three important conclusions: (i)
p53-dependent mechanisms inhibit v-Abl transformation of early B cells;
(ii) the C-terminal region of v-Abl, which is missing from p90, is not
required for the early B-cell tropism of A-MuLV; and (iii) the
C-terminal region of v-Abl is required to counteract the inhibitory
effect of p53 for transformation in vivo.
v-Abl and p53-dependent inhibition of transformation.
A-MuLV
transformation of BMCs in vitro was more than sevenfold higher in
p53/ cells. In vivo onset of tumor formation and tumor
progression increased and survival time decreased following A-MuLV
infection in p53/ animals (Table 1 and Fig. 1). These
data show that a p53-dependent step(s) inhibits
v-abl-dependent transformation in normal cells. A similar
result has been reported for the related human oncogene bcr-abl (41). The data are also consistent with
previous reports that p53/ cells are more susceptible
to transformation by other oncogenes, including those activated by
M-MuLV insertion (2), Wnt-1 (7), E1A
(25), and oncogenic Ras (37). In addition, our
data are consistent with the finding that more than 40% of pre-B-cell
lines transformed in vitro with v-Abl develop mutations in p53
(43) and with the recent report that p53 is required for
apoptotic crisis during transformation of primary pre-B cells by A-MuLV (44).
/ cells to v-Abl-dependent
transformation. p53/ mice have a higher percentage of
pre-B cells (B220+ IgM) in their bone marrow
compared to p53+/+ mice, thus presenting more targets for
v-Abl (40). However, the percentage increase, which is less
than twofold (40), cannot fully explain the sevenfold
increase in transformation of p53/ bone marrow cells in
vitro (Table 1). Another possibility is that further mutational events
are required for v-Abl-dependent transformation, and these mutations
may be more likely to occur in p53/ cells since they
are impaired for cell cycle regulation and apoptosis, which normally
allow DNA repair or cell removal in response to DNA damage
(11). These mechanisms are not mutually exclusive with each
other or with the mechanism discussed above of a v-Abl-dependent activation of p53 via p19ARF. We suspect that
multiple p53-dependent mechanisms may combine to give the increased
susceptibility to v-Abl transformation which we have observed.
The ability of p90v-Abl to transform p53/ early B cells
in vivo but not in vitro is intriguing because most previously studied mutants of v-Abl have shown similar transformation efficiency for pre-B
cells in vivo and in vitro. One explanation for the difference between
in vitro and in vivo transformation is the possibility that in vivo
transformation allows more time for additional genetic events to occur
and that the particular functions missing in the p90 mutant are
unusually dependent on these changes. We also noted that Southern
analysis of one p53/ pre-B cell tumor formed by p160
revealed that the tumor was clonal, consistent with the idea that
genetic changes, in addition to inactivation of p53-dependent
apoptosis, are required for v-Abl transformation.
Early B-cell tropism of A-MuLV and role of the C-terminal region of
v-Abl.
One of the fascinating paradoxes of v-Abl biology is that
although A-MuLV (pseudotyped by M-MuLV) can bind to and infect most cell types, tumors that develop from mice infected with A-MuLV are
almost exclusively pro- or pre-B-cell lymphomas (34). We originally suspected that since early B cells undergo a specific DNA
rearrangment of their immunoglobulin genes, p53 regulation might be
different in these cells and that differential regulation of p53 might
provide an explanation for the pre-B-cell tropism of A-MuLV. However,
our results clearly show that p53 is not required for the pre-B-cell
tropism of A-MuLV. Both in vitro and in vivo, A-MuLV retained its
pre-B-cell tropism in p53/ cells.
/ mice with
A-MuLV-P90A. Thus, we conclude that the C terminus does not confer
B-cell tropism although it appears to be important for efficient
responses in pre-B cells. We suggest that future studies aimed at
understanding B-cell tropism should focus on the protein tyrosine
kinase domain.
Although our data have ruled out a role for the C-terminal region of
v-Abl in B-cell tropism, they have identified an alternate but
important role for the C terminus. A-MuLV-P90A is very defective for
transformation in vivo in normal animals but regains the phenotype of
an acutely transforming virus in p53/ mice (Fig. 1B).
These data indicate that the C-terminal region of v-Abl is important
for sending mitogenic signals which counteract p53-dependent growth
arrest or apoptotic signals. This activity of v-Abl may be required for
transformation of primary cells, where p53-dependent apoptotic pathways
are intact, but not of immortalized cells such as 3T3 cells.
It is clear that v-Abl activates multiple mitogenic signaling pathways.
Some of these, such as the E2F-Myc path, depend on the SH2 and protein
tyrosine kinase portion of the protein (46); however, others
depend on the C-terminal portion and could include activation of
Jak/STAT (5) or other pathways. It seems likely that
A-MuLV-P90A cannot send appropriate mitogenic signals to overcome
p53-dependent growth arrest signals, and thus it is poorly transforming. However, when the p53 pathway is defective, mitogenic signals from the SH2 and tyrosine kinase domains are sufficient to
cause transformation in vivo. It will be important to identify the
C-terminal domains of v-Abl which are involved in sending mitogenic signals.
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ACKNOWLEDGMENTS |
|---|
We are grateful to members of the Calame and Goff laboratories for helpful discussions and to Cristina Angelin-Duclos for critically reading the manuscript. We thank Sharon Boast and Yuming Xu for expert technical assistance.
This work was supported by grant PO1 CA75339 to both S.P.G. and K.C. S.P.G. is an investigator of the Howard Hughes Medical Institute.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: Department of Microbiology, Columbia University, 701 West 168th St., HHSC 1202, New York, NY 10032. Phone: (212) 305-3504. Fax: (212) 305-1468. E-mail: klc1{at}columbia.edu.
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Introduction
Materials and Methods
Results
Discussion
References
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