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NEOPLASIA
From the Center for Biotechnology, College of Science
and Technology, Temple University, Philadelphia, PA; Department of
Clinical Cytology, Medical Center for Postgraduate Education, Warszawa,
Poland; and Department of Pathology and Laboratory Medicine, University
of Pennsylvania, Philadelphia.
BCR/ABL oncogenic tyrosine kinase activates STAT5, which plays an
important role in leukemogenesis. The downstream effectors of the
BCR/ABL Emergence of the Philadelphia chromosome (Ph1)
results from the t(9;22) reciprocal chromosomal translocation present
in most, if not all, patients with chronic myelogenous leukemia
(CML)1,2 and subsets of patients with an acute
myeloblastic leukemia (AML) and acute lymphoblastic leukemia
(ALL).3 This translocation results in the formation of
bcr/abl hybrid genes derived from relocation of the
c-abl gene from chromosome 9 to the bcr gene locus on chromosome 22. The bcr/abl hybrid genes produce
BCR/ABL fusion proteins (p230, p210, and p185) that transform immature hematopoietic cells in vitro4-6 and cause a CML or acute
leukemialike syndromes in mice.7-9 The process of
transformation is accompanied by growth factor
independence,10 reduced susceptibility to
apoptosis,11 and altered motility of the
BCR/ABL-expressing cells.12 The BCR/ABL oncoproteins
display a constitutive tyrosine kinase activity, a feature necessary
for their leukemogenic capacity.13 The BCR/ABL tyrosine
kinase modulates signaling pathways activating several proteins
including signal transducer and activator of transcription 5 (STAT5).14-17 Studies using STAT5 dominant-active and
dominant-negative mutants showed that STAT5 is essential for the
transformation of hematopoietic cells by BCR/ABL.16-19 On
the other hand, experiments performed on murine bone marrow cells from
STAT5 knockout mice (STAT5 KO cells) indicated that although STAT5 was
not essential for BCR/ABL-dependent in vitro transformation, it was
important for development of BCR/ABL-induced myeloid leukemia in
vivo.20 However, the results from STAT5 KO cells should be
interpreted with caution because of the high level of redundancy in the
signaling pathways in hematopoietic cells. Thus, it is possible that
bone marrow cells (BMCs) in surviving STAT5 KO mice21 are
able to develop overlapping pathways, which overcome the absence of
STAT5. In accordance with this speculation, we observed that
BCR/ABL-transformed cells were able to recover partially from
expression of the STAT5B dominant-negative mutant,14
suggesting activation of redundant pathways. In conclusion, STAT5 seems
to play an important role in the oncogenesis induced by BCR/ABL as well
as other oncogenic tyrosine kinases such as TEL/JAK2 and
NPM/ALK.22 The exact mechanisms regulated by STAT5 during
cell transformation remain unclear.
STAT5 belongs to the family of STATs, which are latent transcription
factors that become activated by phosphorylation on tyrosine and also
on serine.23,24 The activated STATs dimerize, translocate to the nucleus, bind specific DNA elements, and induce transactivation of numerous genes. Activated STAT5 enhances the expression of various
proteins including cyclin D1,25,26
bcl-xL,25-27 CIS,28 A1,29
pim-1,30 Id-1,31 OSM,32 c-fos,
and c-jun.23 The role of cyclin D1,33
bcl-xL,16 CIS,34 and c-Jun35 in
BCR/ABL-mediated transformation has already been established. This work
is focused on A1 and pim-1, the 2 proteins regulating cell apoptosis
and proliferation.
A1, a member of the Bcl-2 gene family has been
shown to transiently protect from apoptosis 32Dcl3 hematopoietic cells
upon growth factor withdrawal.29 Bfl-1, the human
homologue of A1, promotes cell survival36 and cooperates
with the E1A oncogene in cell transformation.37 In
addition, Bfl-1/A1 is able to suppress apoptosis induced by tumor
necrosis factor Expression of pim-1 serine/threonine kinase correlated with cell
mitogenesis and survival independent of growth factors.43 Pim-1 synergized with c-Myc in leukemogenesis44 and
enhanced transcriptional activity of c-Myb.45 Both c-Myc
and c-Myb are essential for BCR/ABL leukemogenesis.46-49
In addition, Cdc25A cell cycle phosphatase, a direct transcriptional
target for c-Myc, is a substrate for pim-1 kinase50 and
may tie pim-1-mediated mitogenic signals to the cell cycle machinery.
Pim-1 may also be associated with protection of hematopoietic cells
from apoptosis induced by genotoxic stress or growth factor
withdrawal.51 Thus, pim-1 could potentially be involved in
promotion of the cell cycle progression and inhibition of apoptosis in
BCR/ABL-expressing cells.
We report here that expression of A1 and pim-1 is induced by BCR/ABL
and that both are required in the BCR/ABL-mediated leukemogenesis.
Plasmids
Cells
Inhibition of BCR/ABL kinase ABL kinase inhibitor STI571 (imatinib mesylate [Gleevec])55 was obtained from Novartis Pharma (Basel, Switzerland). Cells (106/mL) were incubated for 24 hours with 1 µM STI571 in the presence of IL-3, then washed and used for experiments.Proliferation and apoptosis Cells (105/mL) were incubated in a growth factor-free medium. Apoptotic cells were detected on cytospin slides by TACS in situ apoptosis detection kit (Trevigen, Gaithersburg, MD). Proliferation was examined by counting the cells excluding trypan blue.Cell cycle analysis Cells (106) were fixed in 70% ethanol for 15 minutes at 4°C, washed, and incubated in 1 mL phosphate-buffered saline (PBS) containing 0.1% NP-40 and 1 mg/mL of DNAse-free RNAse (Boehringer Mannheim, Indianapolis, IN) for 10 minutes at room temperature. DNA was stained by propidium iodide. Cells were analyzed by FACSCalibur (Becton Dickinson, San Jose, CA) using CellQuest Program.Retroviral infections Infections with BMCs were performed as described14,52,53 with some modifications. Briefly, BMCs from mice pretreated with 5-FU were stimulated with stem cell factor (SCF) and IL-3 for 48 hours and then cocultivated with retrovirus-producing Bosc23 packaging cells transfected with the BCR/ABL-IRES-GFP, BCR/ABL -IRES-GFP, or IRES-GFP (control)
retroviral constructs. Nonadherent green fluorescent protein-positive
(GFP+) cells were obtained 72 hours later by cell
sorting. These cells were expanded by 3-day stimulation with SCF plus
IL-3 and subjected to the second round of infection with the viruses
carrying A1 and/or pim-1 cDNA (sense, AS, or point-mutant) and
puromycin- or neomycin-resistance sequences. Control cells were
infected with the retroviruses containing the antibiotic resistance
only. In general, GFP+ cells were cocultivated with the
Bosc23 cells transfected with the retroviral constructs for 72 hours in
the presence of growth factors. To increase the infection efficiency an
equal volume of fresh retroviral supernatant was added to the
cocultivation medium every 24 hours (the retroviral titers were usually
between 1 and 3 × 106 U/mL as determined by measuring
the infection efficiency on Rat-2 cells54). After
infection cells were incubated for 4 days in the presence of growth
factors, G418 and/or puromycin, and then spun down on Lympholyte-M
(Cedarlane Laboratories, Hornby, ONT, Canada) to eliminate dead
cells (about 20%-30% of cells were recovered). GFP+,
G418, and/or puromycin-resistant cells were used for the experiments. In general, cell lines were infected as described.56
32DHN, 32DHN-A1, FD/neo, and FD/mpim44 cells were infected with
BCR/ABL-IRES-GFP, BCR/ABL-IRES-GFP, or IRES-GFP (control)
viruses. 32Dcl3 cells were infected with pMX-puro or pMX-BCR/ABL-puro
retrovirus. Freshly established puromycin-resistant mixed populations
were infected with pim-1(K67M)-IRES-GFP, A1(AS)-IRES-GFP, or IRES-GFP
viruses. GFP+ cells were obtained by sorting and used for
experiments. 32DHN-A1 cells were infected with pMX-pim-1-puro. Freshly
established puromycin-resistant 32DHN-A1 clones overexpressing pim-1
(data not shown) were infected with the BCR/ABL-IRES-GFP or
IRES-GFP retrovirus. GFP+ cells were obtained by sorting
and used for experiments.
Northern analysis Cells were starved from IL-3 and serum (incubation in IMDM supplemented with 0.1% bovine serum albumin [BSA]) for 8 hours. Total RNA was isolated and probed for the presence of A1, pim-1, and GADPH using specific full-length cDNA probes end-labeled with ( 32P)dCTP (NEN Life Science Products, Boston, MA).
Western analysis Cells were solubilized in lysis buffer (10 mM Hepes, pH 7.5, 150 mM NaCl, 1% NP-40, 10% glycerol, 5 mM EDTA, 1 mM -mercaptoethanol, 1 mM phenylmethylsulfonyl fluoride, 50 mM NaF, 1 mM
Na3VO4 and 10 µg/mL each aprotinin and
leupeptin). The lysates were resolved by sodium dodecyl
sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and examined by
Western analysis using primary antibodies recognizing the following
proteins: A1 (T-18 + C-19, Santa Cruz Biotechnology, Santa Cruz,
CA), pim-1 (C-20 + N-16, Santa Cruz), Flag-2 (Sigma Chemical, St
Louis, MO), actin (C-11, Santa Cruz), tyrosine phosphorylated proteins
(P.Tyr; PY20 from Oncogene Research Products, Cambridge, MA, and 4G10
from Upstate Biotechnology, Lake Placid, NY), c-ABL (Ab-3, Oncogene),
active caspase 3 (CM1, generous gift from IDUN Pharmaceuticals, La
Jolla, CA), Bad (K-17, Santa Cruz), Bax (Ab-5, Oncogene), Bcl-2 (N-17,
Santa Cruz), and Bcl-xL (Transduction Laboratories, Lexington, KY).
Species-specific secondary antibodies linked to the horseradish
peroxidase (HRP) were from Amersham Life Sciences (Arlington Heights,
IL). Bands were detected with an enhanced chemiluminescence (ECL) kit
(Amersham Life Sciences).
pim-1 kinase reaction Kinase reaction was done essentially as described by Mochizuki and colleagues.50 Briefly, pim-1 was immunoprecipitated from the total cell lysates and reactions were carried out in a 30-µL volume containing 25 mM Hepes (pH 7.5), 10 mM MgCl2, 0.5 mM dithiothreitol, 10 µCi (0.37 MBq) [ -32P]
adenosine triphosphate (ATP), 10 µM ATP, and 10 µg histone H1
(Roche Molecular Biochemicals, Indianapolis, IN). The samples were
incubated at 22°C for 30 minutes and then reactions were terminated
by the addition of 30 µL 2 times sample buffer (100 µM Tris-HCl
[pH6.8], 4% SDS, 20% glycerol, 10% 2-mercaptoethanol, and 0.2%
bromophenol blue). Samples were subjected to SDS-PAGE, followed by autoradiography.
Leukemogenesis in mice C57Bl/6 mice (Taconic Farms, Germantown, NJ) received total body irradiation (450 rads). The next day they were injected intravenously with 105 GFP+ BMCs infected with retroviruses carrying BCR/ABL (WT or mutant)-IRES-GFP followed
by A1 and/or pim-1 cDNAs. Terminally ill mice were killed and examined
for development of leukemia as described.14,53 In brief,
various organs (spleen, liver, lymph nodes, brain, lungs, kidneys,
gastrointestinal tract, and skin) were harvested, fixed, embedded,
sectioned, stained, and examined under the microscope. A chloroacetate
esterase (Leder) staining confirmed myeloid differentiation of
the leukemic cells in the selected tissue sections. Animal studies were
approved by the Institutional Animal Care and Use Committee at
Temple University.
The expression of A1 and pim-1 is regulated by BCR/ABL SH3+SH2-STAT5 pathway Our previous study revealed that signaling by BCR/ABL and in particular by its SH3+SH2 region activated STAT5, a signaling step essential for the BCR/ABL-mediated leukemogenesis.14 To define in more detail this novel cell transforming pathway, we examined expression of the 2 downstream effectors of STAT5: A1 and pim-1.29,30For this purpose, messenger RNA (mRNA) and protein levels of A1 and
pim-1 were determined in 32Dcl3 parental cells and clones expressing
either BCR/ABL WT, BCR/ABL
Role of A1 and pim-1 in BCR/ABL-mediated growth factor independence Prevention of cell apoptosis and induction of growth factor independence are among the major functions of BCR/ABL.57 To examine the role of A1 and pim-1 in these processes, 2 types of experiments were performed. First, A1 or pim-1 proteins were up-regulated in cells expressing the BCR/ABL mutant, and second,
A1 protein and pim-1 kinase were down-modulated in the
BCR/ABL+ cells by introduction of the A1 AS cDNA or
kinase-deficient mutant of pim-1 (K67M).
Elevation of the expression of A1 protein in 32DHN-A1 cells to the
level observed in BCR/ABL+ counterparts (Figure
2A, left panel) caused only a modest
protection from apoptosis in growth factor-free medium (Figure 2A,
right panel). Eventually all cells died in apoptosis after 5 days of incubation without growth factor. Similar up-regulation of A1 in the
BCR/ABL
Ectopic expression of pim-1 protein in FD/mpim44 cells at the
level comparable to one seen in the BCR/ABL WT-transfected FD cells
(Figure 3A) protected these cells from
apoptosis in the growth factor-free medium during the first 3 days of
culture, but eventually almost all cells died by day 5 (Figure 3B).
Increased expression of pim-1 in the BCR/ABL
Because A1 seems to be preferentially involved in protection from apoptosis29 and pim-1 appears to be engaged in both cell proliferation and apoptosis,43 we decided next to determine if the functions of A1 and pim-1 are complementary or overlapping. Coexpression of A1 and pim-1 in 32DHN cells (Figure
4A) delayed apoptosis in the absence of
IL-3, but almost all cells eventually died after 5 days of culture
(Figure 4B). However, the coexpression of A1 and pim-1 rescued the
factor-independent growth of the cell transformation-defective
BCR/ABL
Both A1 and pim-1 are required for BCR/ABL-mediated leukemogenesis To determine if A1 or pim-1 or both play an essential role in BCR/ABL-mediated transformation of normal BMCs, we tested whether overexpression of A1 or pim-1 rescues the impaired transforming capacity of BCR/ABL mutant, and whether down-modulation of A1 or
pim-1 inhibits cell transformation mediated by BCR/ABL WT. BMCs from
5-FU-treated mice were infected with retroviral vectors carrying
several different forms of BCR/ABL, A1, and pim-1, and analyzed in the
in vitro colony formation assay in the growth factor-free medium. BMCs
infected with BCR/ABL WT formed numerous colonies in the absence of
IL-3 and many more arose in the presence of the threshold concentration
of IL-3 (Figure 5A, group 5). The control, empty retrovirus-infected cells, did not form any colonies in
the absence of IL-3 and only a few grew in the 0.1 U/mL IL-3 (Figure
5A, group 1). BCR/ABL mutant alone did not induce any IL-3-independent colonies and did not increase the number of colonies in IL-3 in comparison to the control cells (Figure 5A, group 6). Furthermore, no colonies were found in the absence of IL-3 and no
significant colony formation enhancement was noticed in the cells
carrying either A1 or pim-1 (Figure 5, group 2 and group 3, respectively) in comparison to control (Figure 5A, group 1). When
BCR/ABL+ cells were infected with either A1 or pim-1
retrovirus, their clonogenic activity was not affected by A1 or was
only moderately increased by pim-1 (Figure 5A, compare group 7 with
group 6, and group 8 with group 6, respectively). However, coinfection
with both A1 and pim-1 fully restored the impaired transforming
capacity of the BCR/ABL mutant as compared to BCR/ABL WT (Figure
5A, compare group 9 with group 5). Conversely, infection of BCR/ABL WT-expressing BMCs with either A1 AS cDNA or pim-1(K67M) mutant had no
effect, or exerted only a mild effect on their clonogenicity, respectively (Figure 5B, compare group 2 with group 1, and group 3 with
group 1, respectively). However, coinfection with both A1
antisense + pim-1(K67M) mutant exerted a profound negative effect
on the BCR/ABL-induced colony formation (Figure 5B, compare group 4 with group 1).
To determine whether A1 and pim-1 also play an essential role in the
BCR/ABL-mediated leukemogenesis in vivo, preirradiated syngeneic mice
were injected with BMCs infected with BCR/ABL, A1, or pim-1 cDNAs as
described above. All mice inoculated with the cells infected with
BCR/ABL WT succumbed to leukemia (median survival time [MST] of the
mice ± SD = 4.2 ± 0.3 weeks; Figure 6A). Histologic examination of the
multiple organs (spleen, liver, lymph nodes, lung, skin, central
nervous system) revealed the presence of AML in most organs. There was
considerable variability in the degree of blast maturation among the
mice as well as various involved sites. In one case, the histology
resembled more transforming CML rather than an overt acute leukemia.
All of the examined organs showed diffuse leukemic infiltrates and
tissue destruction. The least differentiated cases displayed the
highest mitotic and single-cell necrosis rates and areas of zonal
necrosis. Myeloid origin of the blasts was confirmed in such cases by
chloroacetoesterase stain. BMCs infected with the BCR/ABL
A1 and pim-1 work in concert to regulate apoptosis and cell cycle A1 and pim-1 are potent regulators of apoptosis and cell cycle progression.29,43 Because they collaborate in BCR/ABL leukemogenesis, we decided to examine their effect on expression of proapoptotic and antiapoptotic genes and on cell cycle progression in the BCR/ABL cells. After parental and BCR/ABL-, A1-, and/or pim-1-carrying cells (cell clones are described in the legend to Figure 4) were starved from IL-3, time-dependent activation of caspase 3 was detected in the parental, A1, pim-1, BCR/ABL, and
BCR/ABL + A1 cells, whereas in the BCR/ABL WT, A1 + pim-1, BCR/ABL + pim-1, and BCR/ABL + A1 + pim-1 cells caspase 3 was not activated during 12 hours of
starvation from IL-3 (Figure
7A).
The high levels of unphosphorylated Bad protein correlated with
casapse-3 activation, whereas Bax protein was generally not affected.
Importantly, the antiapoptotic proteins Bcl-2 and Bcl-xL remained
significantly up-regulated despite the IL-3 starvation in the BCR/ABL
WT cells, but only the high expression of Bcl-2 was preserved in pim-1,
A1+pim-1, and BCR/ABL Cell cycle analysis revealed that in the absence of IL-3 parental cells
were composed almost totally of cells containing subdiploid amount of
DNA (a signature of apoptosis), whereas the DNA content and cell cycle
progression profile of the BCR/ABL WT cells were not significantly
affected by the absence of IL-3 (Figure 7B). In turn, the IL-3-starved
BCR/ABL
Activation of STAT5 seems important for the BCR/ABL-mediated
leukemogenesis, especially for the development of myeloproliferative disease.14-17,20 The mechanisms operating downstream of
the BCR/ABL We speculate that enhanced A1 expression and pim-1-induced up-regulation of Bcl-2 expression could exert synergistic/additive antiapoptotic effects, as described before.29 A1 and Bcl-2 exert their function by heterodimerizing with the proapoptotic proteins to stabilize mitochondrial membranes and prevent the release of cytochrome c.41,42 Therefore, their functions may be simply additive. However, although both A1 and Bcl-2 can heterodimerize with Bax, only Bcl-2 appears to interact with Bad.42,60 Thus, Bcl-2 seems to regulate antiapoptotic pathways, which may not be accessible to A1. Nevertheless, A1+pim-1 cells started to die after 72 hours of starvation, which was preceded by activation of caspase 3 and down-regulation of Bcl-2 (our unpublished data, May 2000). The latter phenomenon was at least partially due to the caspase 3-dependent cleavage of Bcl-2 because of the appearance of characteristic 22-kd Bcl-2 fragment,61 which can further accelerate apoptosis.62,63 In addition to its antiapoptotic effect, BCR/ABL also regulates the
cell cycle.57 Pim-1 may contribute to this process through phosphorylation and activation of Cdc25A.50 Cdc25A, a
phosphatase essential for G1 Thus, it is probable that the combination of the strong antiapoptotic
signaling (A1 and Bcl-2) with the mitogenic signal (Cdc25A and c-Myb)
rescued transforming ability of the BCR/ABL In conclusion, our data demonstrate that A1 and pim-1 complement each other in BCR/ABL-mediated malignant cell transformation. They may, therefore, play an important role in the pathogenesis of CML and other, BCR/ABL-related hematopoietic disorders.
Submitted August 30, 2001; accepted January 25, 2002.
Supported in part by National Institutes of Health (NIH) grants CA83700 and CA89052, by grant RPG 98-348-01 from the American Cancer Society, and by grant 501-2-1-03-97/07 from the Medical Center of Postgraduate Education (all to T.S.), and NIH grant CA89194 to M.A.W. T.S. is a Scholar of the Leukemia and Lymphoma Society.
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: Tomasz Skorski, Center for Biotechnology, Temple University, Bio-Life Sciences Bldg, Rm 419, 1900 N 12th St, Philadelphia, PA 19122; e-mail: tskorski{at}astro.temple.edu
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Top
Abstract
Introduction
STAT5 pathway remain poorly defined. We show here that
expression of the antiapoptotic protein A1, a member of the Bcl-2
family, and the serine/threonine kinase pim-1 are enhanced by BCR/ABL.
This up-regulation requires activation of STAT5 by the signaling from
SH3+SH2 domains of BCR/ABL. Enhanced expression of A1 and pim-1 played
a key role in the BCR/ABL-mediated cell protection from apoptosis. In
addition, pim-1 promoted proliferation of the BCR/ABL-transformed
cells. Both A1 and pim-1 were required to induce interleukin
3-independent cell growth, inhibit activation of caspase 3, and
stimulate cell cycle progression. Moreover, simultaneous up-regulation
of both A1 and pim-1 was essential for in vitro transformation and in
vivo leukemogenesis mediated by BCR/ABL. These data indicate that
induction of A1 and pim-1 expression may play a critical role in the
BCR/ABL-dependent transformation.
(Blood. 2002;99:4531-4539)
) or presence (+) of the threshold concentration (0.1 U/mL) of
murine recombinant IL-3. Results (mean ± SD) are from 3 experiments.
B
(NF-