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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 9 (May 1), 1998:
pp. 3333-3339
Myc Is Essential for Transformation by TEL/Platelet-Derived Growth
Factor Receptor  (PDGFR)
By
Marie-Françoise Bourgeade,
Anne-Sophie Défachelles, and
Yvon E. Cayre
From U417 Institut de la Santé et de la Recherche
Médicale (INSERM), Hôpital Saint-Antoine, Paris, France;
and the Department of Microbiology/Immunology, Bluemle Life Sciences
Building, Thomas Jefferson University, Philadelphia, PA.
 |
ABSTRACT |
The t(5;12) translocation identified in patients with
chronic myelomonocytic leukemia (CMML)
encodes a TEL/platelet-derived growth factor receptor  (PDGFR) fusion protein. A key hypothesis for how the TEL/PDGFR
fusion protein would function as an oncogene is that it represents a
constitutively active version of the normal PDGFR. A link between
the function of the t(5;12)-encoded TEL/PDGFR fusion protein and Myc
expression is suggested by the fact that Myc is induced by PDGF and is
essential for entry of cells into the S phase of the cell cycle. We
here show that the kinase activity of TEL/PDGFR is necessary for
Ba/F3 cells to acquire interleukin-3 (IL-3) independence and that, in
contrast to their untransfected counterpart, Ba/F3 cells stably
transfected with TEL/PDGFR maintain a high level of Myc expression
after removal of IL-3. Using dominant negative mutants of Myc, we show
that a threshold of active Myc is essential for TEL/PDGFR to
transform Ba/F3 and Rat-1 cells. The findings that the kinase activity
of TEL/PDGFR and a threshold of active Myc are involved in
TEL/PDGFR transformation may allow for the development of
therapeutic strategies in patients with t(5;12)+ CMML
using specific inhibitors of the PDGFR kinase as well as compounds
designed to interfere specifically with Myc.
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INTRODUCTION |
THE t(5;12) TRANSLOCATION identified in
patients with chronic myelomonocytic leukemia fuses the TEL
gene, a member of the ets family of transcription factors on
chromosome 12, to the intramembranous and tyrosine kinase domains of
the platelet-derived growth factor receptor (PDGFR) on
chromosome 5.1 The TEL sequence encoded by the TEL/PDGFR
transcript has lost the DNA binding domain but has retained the
transactivation domain in which a 5 Helix-Loop-Helix (HLH) portion is
highly conserved among a subset of ETS proteins though it has only weak
homology to the HLH domain of the b-HLH family of transcription
factors.2 This ETS protein HLH domain is known to be
essential for full transactivating function.3,4 In fact,
deletion of the HLH domain of TEL inhibits constitutive activation of
the PDGFR kinase as well as mitogenic properties of
TEL/PDGFR.5,6
A critical step in activation of native PDGFR is initiated by the
binding of PDGF which induces dimerization of two adjacent PDGF
receptors followed by their transphosphorylation at specific tyrosine
residues. These phosphorylated residues provide binding sites for
specific SH2 domains of effector proteins.7,8 The binding
of effector proteins to the activated PDGFR results in the activation
of multiple signal transduction pathways.9 In addition to
the well elucidated "ras pathway," necessary for
PDGF-stimulated DNA synthesis,10 a novel pathway has been
identified which uses the nonreceptor tyrosine kinase Src and is also
induced by PDGF.11 Both pathways contribute to the cascade
of transcriptional responses that signal an irreversible commitment to
enter the S phase of the cell cycle. Although a well-known target of
the ras pathway is the fos gene,10 the target of
the Src pathway is the Myc gene, which results in a Myc
protein expression throughout the cell cycle, whereas c-fos is rapidly
downregulated after induction.12 Because Myc expression was
shown to be increased by PDGF and to be essential to induce DNA
synthesis after PDGF stimulation, we investigated whether Myc was
constitutively induced by TEL/PDGFR in Ba/F3 hematopoietic cells and
rat embryo fibroblasts.
We here report that TEL/PDGFR protein expression results in
increased levels of Myc expression in Ba/F3 cells. Moreover, a decrease
of active endogenous Myc by expression of dominant negative mutants of
Myc reversed the capacity of TEL/PDGFR to induce soft-agar colony
formation by Rat-1 cells and reversed the interleukin-3 (IL-3)
independence of TEL/PDGFR-expressing Ba/F3 cells cultured in low
serum conditions.
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MATERIALS AND METHODS |
Vectors.
Full-length TEL/PDGFR and TEL/ABL cDNAs inserted in the
pSR /MSV/TK/neo retroviral expressing vector were provided by T. Golub (Harvard University). The MycRX and Max2RX mutants have already
been described13 and were provided by B. Amati (ISREC, Lausanne).
Cell transfection and transformation assays.
The IL-3-dependent leukemia murine BaF3 cell line was cultivated in
RPMI 1640 supplemented with 10% fetal calf serum (FCS) and 5% WEHI-3B
cell culture supernatant as a source of IL-3. Cells (2 × 107/transfection) were transfected with the
different vectors (10 µg/transfection) by electroporation at 0.28 kV
and 960 microfarads using a Bio-Rad Gene Pulser apparatus. Cells
transfected with TEL/PDGFR were selected 48 hours after transfection
by G418 selection (400 µg/mL) followed by IL-3 deprivation, whereas
cells transfected with the control vector were only selected with G418.
Cells transfected with MycRX or the control pBabe vector were selected
for resistance to puromycin (12.5 µg/mL). For transformation assays,
the ability of TEL/PDGFR-transfected cells to grow in the absence of
IL-3 was assessed by counting the cells at different times after IL-3 removal using a Coulter counter. The rat fibroblasts (Rat-1) expressing dominant negative mutants of Myc (MycRX, Max2RX) were a gift from B. Amati (ISREC Lausanne). They were cotransfected with the
pSR/MSV/TK/neo vector containing the TEL/PDGFR cDNA by calcium
phosphate precipitation and then selected with G418 (400 µg/mL) for
12 to 15 days. For transformation assays, 2 × 104
G418-resistant cells were plated in soft agar and colony formation was
assessed after 2 weeks of culture. TEL/PDGFR protein expression was
analyzed in G418-resistant cells by Western blotting.
Western blotting.
Cells were lysed in 20 mmol/L Tris pH 6.7, 0.5% sodium dodecyl sulfate
(SDS), boiled for 3 minutes, and treated with 1 U of Benzon nuclease
for 10 minutes at room temperature. Total cell lysates were subjected
to SDS-polyacrylamide gel electrophoresis and electrophoretically
transferred to nitrocellulose filters (at 50 mA for 15 hours in 20 mmol/L Tris, 150 mmol/L glycine, 20% [vol/vol] ethanol, and 2%
SDS). Western blottings were performed with anti-PDGFR polyclonal
antibody (UBI, Lake Placid, NY), anti-Myc or anti-Max polyclonal
antibodies (Santa Cruz Biotechnology, Inc, Santa Cruz, CA), or
antiphosphotyrosine monoclonal antibody (Transduction Laboratories,
Lexington, KY). Blots were revealed with sheep anti-mouse or
anti-rabbit IgG horseradish peroxidase-linked antibodies and enhanced
chemiluminescence (ECL; Amersham, Little Chalfont, Bucks, UK). The
nitrocellulose filters were exposed for various times to ECL film
(Amersham).
RNA preparation and Northern blot analysis.
RNA was extracted using the RNA-easy Kit (Quiagen Inc, Valencia, CA).
For Northern blot analysis, 15 µg of total RNA were denaturated,
mixed with ethidium bromide to a final concentration of 60 µg/mL, and
fractionated on a 0.9% formaldehyde agarose gel. RNA was transferred
to a Hybond N nylon membrane (Amersham). After UV cross-linking, RNAs
were hybridized for 18 hours at 42°C with 107 cpm of
32P-labeled cDNAs in 50% formamide, 5 × SSPE (0.75 mol/L NaCl, 5 mmol/L EDTA, 50 mmol/L sodium
phosphate, pH 7.4) and 5 × Denhardt's solution. Filters were then
washed twice at room temperature in 2 × SSC (0.30 mol/L
NaCl, 30 mmol/L sodium citrate, pH 7) and 0.1% SDS, and once in
0.1 × SSC and 0.1% SDS at 50°C for 1 hour. Kodak XAR-5
films (Eastman Kodak Co, Rochester, NY) and Philips ultraS intensifying
screens (Philips, Eindhoven, The Netherlands) were used for
autoradiography.
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RESULTS |
Transformation of Ba/F3 cells by TEL/PDGFR requires the
kinase activity: Inhibition by a PDGFR selective
tyrosine kinase inhibitor.
IL-3-dependent Ba/F3 cells were transfected with the pSR/MSV/TK/neo
retroviral vector containing or not the TEL/PDGFR full-length cDNA.1 Consistent with the results recently reported by
Carroll et al,5 we found that cells expressing the
TEL/PDGFR protein grew in the absence of IL-3 and that the fusion
protein was constitutively phosphorylated (data not shown). To
determine whether this phosphorylation was involved in the transforming
capacity of TEL/PDGFR, we used a protein tyrosine kinase inhibitor
(CGP53716) that shows selectivity for the PDGFR.14 As shown
in Fig 1a, treatment of
TEL/PDGFR-expressing Ba/F3 cells with 0.3 µmol/L CGP53716
completely inhibited their growth in the absence of IL-3, whereas this
growth was restored by the addition of IL-3. This inhibitor did not
modify the growth of TEL/ABL-expressing Ba/F3 cells even in the absence
of IL-3. As expected because CGP53716 inhibits ABL
tyrosine kinase at 3 µmol/L,14 a slight decrease in cell
growth was observed at this concentration when TEL/ABL-expressing Ba/F3
cells were cultured in the absence of IL-3.
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| Fig 1.
Growth inhibition of TEL/PDGFR-expressing Ba/F3 cells
by CGP53716. (a) TEL/PDGFR- or TEL/ABL-expressing cells were seeded at a density of 3.105 cells/mL with or without IL-3 and in
the presence of different concentrations of CGP53716 (provided by
CIBA-GEIGY, Basel, Switzerland). Cell numbers were determined after 24 hours of culture. ( ), TEL/PDGFR IL-3 ; ( ),
TEL/PDGFR IL-3+; ( ), TEL/ABL IL-3;
(X), TEL/ABL IL-3+. (b) In contrast to TEL/PDGFR- or
TEL/ABL-expressing Ba/F3 cells, control Ba/F3 cells were maintained
with IL-3. These cells were either untreated ( ) or treated (+) for
18 hours with 0.3 µmol/L of CGP56713. Cell lysates were analyzed by
Western blotting using an antiphosphotyrosine antibody.
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To study the PDGFR tyrosine kinase specificity of CGP53716 in Ba/F3
cells, Western blot analysis of cell extracts from control Ba/F3 cells
maintained with IL-3 as well as from TEL/PDGFR- or TEL/ABL-expressing cells maintained without IL-3 and either untreated or treated for 18 hours with 0.3 µmol/L CGP53716 were
performed using antiphosphotyrosine antibodies. In control Ba/F3 cells, CGP53716 did not inhibit the overall pattern of tyrosine
phosphorylation (Fig 1b). In TEL/PDGFR-expressing cells, a band of
~100 kD, likely to correspond to the phosphorylated
fusion protein, was no longer readily detected after
treatment with CGP53716. In TEL/ABL-expressing cells, an ~180-kD
protein likely to correspond to the TEL/ABL15 protein
remained unchanged after treatment with CGP53716. A lower molecular
weight band previously described to be highly phosphorylated in these
cells14 also remained unchanged. Collectively, these results reinforced the view that CGP53716 specifically inhibited PDGFR tyrosine kinase activity and that the kinase activity harbored by the PDGFR part of the TEL/PDGFR protein was involved in the transforming activity of this fusion protein.
Myc expression is increased in TEL/PDGFR-expressing Ba/F3 cells.
Because the Myc oncoprotein is one of the intermediate early genes
induced by PDGF in various cell lines, its expression was tested in
Ba/F3 cells expressing or not the TEL/PDGFR protein. Because IL-3
has been shown to induce Myc,16,17 cell lysates were
prepared from exponentially growing Ba/F3 cells cultured for 24 hours
in the absence or in the presence of IL-3 and Myc expression was
assessed by Western blotting. In the presence of IL-3, Ba/F3 cells
expressed high levels of Myc independently of TEL/PDGFR protein
expression. However, whereas Myc protein expression was maintained at
high levels in cells expressing TEL/PDGFR protein cultured without
IL-3 for 24 hours, it was dramatically decreased in cells transfected
with the control vector (Fig 2a). This was correlated with Myc mRNA levels (Fig 2b).
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| Fig 2.
Myc mRNA and protein expression in Ba/F3 cells expressing
or not TEL/PDGFR. (a) Cells were cultured for 24 hours
in the presence (+) or in the absence () of IL-3. Cell lysates
were analyzed by Western blotting using an anti-Myc antibody. (b) Total
RNA from Ba/F3 cells transfected with either the control vector or TEL/PDGFR and cultured for 18 hours without IL-3 were analyzed by
Northern blotting using an Myc cDNA probe. Lower panel is ethidium bromide staining of the 28S ribosomal RNA used as a control of RNA
concentration in each lane. (c) Untransfected Ba/F3 cells as well as
TEL/PDGFR-expressing cells were cultured for 18 hours in the
presence (+) or in the absence () of IL-3, respectively, with
(+) or without () 0.3 µmol/L of CGP53716. Cell lysates were analyzed by Western blotting using an anti-Myc antibody.
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Furthermore, CGP53716 (0.3 µmol/L) did not affect Myc protein
expression induced by IL-3 in untransfected Ba/F3 cells, whereas it
strongly decreased this expression in TEL/PDGFR-expressing Ba/F3
cells cultured without IL-3 (Fig 2c). These results provided further
evidence that in TEL/PDGFR-expressing cells, Myc expression was a
direct consequence of TEL/PDGFR activation.
The fact that Myc expression was increased in TEL/PDGFR-expressing
cells and was dependent on TEL/PDGFR kinase activity strongly
suggested that the fusion protein activated the same pathways as the
PDGFR.
A dominant negative mutant of Myc decreases cell growth of
TEL/PDGFR-expressing Ba/F3 cells.
To determine if Myc was essential for transformation by TEL/PDGFR,
we overexpressed dominant negative mutants of Myc in
TEL/PDGFR-expressing Ba/F3 and rat fibroblast (Rat-1) cells. The Myc
mutants (MycRX and Max2RX) used in this study were as
described.13 Briefly, Myc and Max heterodimerize and bind
DNA through basic HLH leucine zipper (b-HLH-LZ) motifs. Myc mutants
were generated by reciprocal exchange of b-HLH-LZ regions. MycRX
contains the b-HLH-LZ region of Max and Max2RX contains the b-HLH-LZ
region of Myc. MycRX sequesters Myc into inactive complexes whereas
Max2RX forms stable binding complexes with wild-type Max. Because MycRX
and Max2RX mutants heterodimerize, endogenous Myc activity is restored
when both mutants are coexpressed in the cells.17 These Myc
mutants as well as other Myc mutants18 behave as strong
dominant suppressors of Myc transforming activity by decreasing
endogenous active Myc protein. Because TEL/PDGFR-expressing Ba/F3
cells were poorly receptive to secondary transfection, Ba/F3 cells were
first transfected with MycRX mutant, selected for puromycine
resistance, and subsequently transfected with TEL/PDGFR and selected
for G418 resistance.
To detect MycRX protein expression, we used an antibody directed
against the carboxy terminal of Max which included the
b-HLH-LZ domain. Western blot analysis indicated that an ~67-kD
protein was revealed by this antibody in Ba/F3 cells cotransfected with TEL/PDGFR and MycRX but not in the TEL/PDGFR-transfected
counterparts (Fig 3a). In the absence of
IL-3, MycRX and endogenous Myc expression levels were compared by
Western blotting using an antibody directed against the N-terminal part
of Myc. This antibody recognizes both MycRX and the endogenous Myc.
Because both proteins have similar molecular weights, levels of MycRX
expression were assessed by measuring an increased Myc hybridization
signal. In cells cultured in medium containing 10% FCS, the level of
MycRX expression was not sufficient to match the level of the
endogenous Myc. Reduced endogenous Myc levels were obtained by
cultivating the cells at 1% FCS concentration so that MycRX expression
levels were about two times higher than endogenous Myc and likely to
sequester part of the endogenous Myc (Fig 3b). Under these conditions
and in contrast to the results observed in cells cultured in 10% FCS, cells coexpressing TEL/PDGFR and MycRX did not grow in IL-3-free medium compared with their counterparts cotransfected with TEL/PDGFR and the control vector (Fig 3c). Under the same conditions, Ba/F3 cells
transfected with MycRX alone were able to grow in the presence of IL-3.
This result suggested that TEL/PDGFR-expressing Ba/F3 cells were
unable to grow in the absence of IL-3 when endogenous Myc was expressed
at a level where MycRX exerted its dominant negative effect and thus
decreased the amount of active Myc in the cell.
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| Fig 3.
Myc expression and cell growth of TEL/PDGFR Ba/F3
cells expressing or not MycRX. (a) Protein extracts from Ba/F3 cells
either transfected with TEL/PDGFR or cotransfected with TEL/PDGFR
and MycRX were analyzed by Western blotting using an antibody directed against the C-terminal part of Max. (b) TEL/PDGFR-transfected Ba/F3
cells expressing or not expressing MycRX were cultured
for 24 hours with 1% or 10% FCS, and cell lysates were analyzed by Western blotting using an Myc antibody directed against the N-terminal part of Myc. (c) TEL/PDGFR-transfected Ba/F3 cells expressing or not
expressing MycRX were seeded at a density of
105 cells/mL in the absence of IL-3 and in the presence of
either 1% or 10% FCS. Cell numbers were determined at different times of culture. Data represent the mean ± SD of three independent experiments (*P < .0001 v TEL/PDGFR). (),
TEL/PDGFR; ( ), TEL/PDGFR/MycRX.
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Transforming capacity of TEL/PDGFR is inhibited by a dominant
negative mutant of Myc in Rat-1 cells.
As an additional approach to show that Myc was essential for
TEL/PDGFR-induced transformation, we used Rat-1 cells stably expressing the Myc mutants at a level sufficient to reduce the endogenous Myc in 10% culture conditions. The Rat-1 cells used in our
studies were expressing either Max2RX or MycRX/Max2RX. Because a normal
activity of Myc is restored in Rat-1 cells expressing both
mutants,17 these cells were used as positive controls in our experiments. We were not able to efficiently express the
TEL/PDGFR protein in Rat-1 cells as well as in Rat-1 cells
expressing MycRX. Therefore, Rat-1 cells expressing either Max2RX or
MycRX/Max2RX were transfected with TEL/PDGFR. After 2 weeks of
selection with G418, TEL/PDGFR expression was analyzed in the
resistant cells by Western blotting. This expression was similar for
both Max2RX- and MycRX/Max2RX-expressing Rat-1 cells (data not shown).
Resistant cells were plated in soft agar and the number of colonies was scored after 15 to 18 days of culture. Only cells coexpressing MycRX/Max2RX and TEL/PDGFR were capable of forming colonies in soft
agar. This indicated that expression of a dominant negative mutant of
Myc could reverse the transforming potential of TEL/PDGFR in Rat-1
cells (Fig 4).
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| Fig 4.
Expression of a dominant negative mutant of Myc impairs
soft-agar colony formation by TEL/PDGFR. The Rat-1 expressing
dominant negative mutants of Myc (MycRX, Max2RX) and transfected with
the TEL/PDGFR vector or the control vector were plated in soft agar and the formation of colonies was assessed after 2 weeks of culture. (a) Rat-1 MycRX/Max2RX, (b) Rat-1 MycRX/Max2RX expressing TEL/PDGFR, (c) Rat-1 Max2RX, (d) Rat-1 Max2RX expressing TEL/PDGFR, (e) Number
of colonies per dish. Only the colonies < 0.3 mm were counted. This
is representative of three independent experiments.
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DISCUSSION |
Our results indicate that the pathway leading to Myc expression is
activated by TEL/PDGFR in Ba/F3 cells. Activation of the PDGFR by
its ligand initiates several signal transduction cascades of which at
least one leads to the transcriptional activation of the Myc oncogene.
An active src kinase is necessary for this activation and for PDGF to
induce DNA synthesis.11 Using mutants from the src family
kinase, we are currently investigating whether the same processes are
involved in the activation of Myc by PDGFR and TEL/PDGFR.
Alternatively, overexpression of Myc in TEL/PDGFR-expressing Ba/F3
cells may be mediated by cytokines induced by the fusion protein. It
has been reported that overexpression of PDGF B
profoundly perturbs hematopoiesis in vivo producing a
myeloproliferative syndrome19 and that this effect of PDGF
was mediated by the induction of IL-1.20 However, this
is unlikely in the case of TEL/PDGFR because culture supernatants of
TEL/PDGFR-transfected BaF3 cells did not provoke the growth of
untransfected BaF3 cells (data not shown).
Using a dominant negative mutant of Myc, we showed that increased Myc
expression was involved in TEL/PDGFR transformation and that a
threshold of active Myc was essential for TEL/PDGFR to transform
Ba/F3 and Rat-1 cells. Because Myc is known to induce cell entry into
the S phase of the cell cycle, it would be of interest to investigate
the cell cycle stages of TEL/PDGFR-transformed cells expressing or
not dominant negative mutants of Myc. Previous studies
have indicated that Myc is essential for transformation by
BCR/ABL.21 The discovery that Myc is also
essential in TEL/PDGFR transformation extends the repertoire of Myc
action in human leukemia.
The implication of the Myc pathway in the transformation of Rat-1 cells
by TEL/PDGFR is unlikely to reflect the whole transformation process
because overexpression of Myc alone does not transform fibroblasts.22 Carroll et al5 have indicated
that other PDGFR kinase-dependent signaling pathways are also
activated by TEL/PDGFR. Additionally, we have found that
TEL/PDGFR induces an increased binding of nuclear factors to the AP1
site (data not shown). However, so far, none of these pathways have
been identified as being involved in the TEL/PDGFR transforming
capacity.
Recent results have shown that TEL-induced oligomerization is essential
for the activation of the tyrosine kinase activity and mitogenic
properties of TEL/PDGFR.5,6 We have shown that CGP53716,
a specific inhibitor of the PDGFR kinase, reverses IL-3 independence
in TEL/PDGFR-expressing Ba/F3 cells. This reinforces the view that
constitutive activation of the PDGFR is involved in the transforming
potential of the TEL/PDGFR fusion protein. It has been reported that
CGP56716 has an antitumor activity using v-sis overexpressing
3T3 cells, showing that it is selective for inhibition of PDGF-driven
tumor growth in vivo.13 It would therefore be of interest
to develop animal models to explore the effect of this inhibitor on
TEL/PDGFR-driven tumor growth.
The findings that the kinase activity of TEL/PDGFR and a threshold
of active Myc are involved in TEL/PDGFR transformation may allow for
the development of therapeutic strategies using specific inhibitors of
the PDGFR kinase as well as compounds designed to interfere
specifically with Myc.
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FOOTNOTES |
Submitted July 7, 1997;
accepted December 10, 1997.
Supported by INSERM and by Grant No. CA43225-10 from the National
Institutes of Health (Y.E.C.). A-S.D. is a fellow of the Association
pour la Recherche Contre le Cancer (ARC).
Address reprint requests to Yvon E. Cayre, U417 INSERM, Hôpital
Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75012 Paris, France.
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.
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ACKNOWLEDGMENT |
We thank Dr T. Golub for TEL/PDGFR and TEL/ABL cDNAs and Dr B. Amati
for MycRX and Max2RX cDNAs and for the infected Rat-1 cells. We also
thank Drs Golub and Amati for their critical reading of the manuscript
and Dr E. Buchdunger (CIBA-GEIGY, Basel) for the gift of
CGP53716.
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Abstract
Introduction
Abstract