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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 90 No. 12 (December 15), 1997:
pp. 4947-4952
CGP 57148, a Tyrosine Kinase Inhibitor, Inhibits the Growth of Cells Expressing BCR-ABL, TEL-ABL, and TEL-PDGFR Fusion Proteins
By
Martin Carroll,
Sayuri Ohno-Jones,
Shu Tamura,
Elisabeth Buchdunger,
Jürg Zimmermann,
Nicholas B. Lydon,
D. Gary Gilliland, and
Brian J. Druker
From the Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland, Oregon; Oncology Research Department, Novartis, CH-4002, Basel, Switzerland; and Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
 |
ABSTRACT |
CGP 57148 is a compound of the 2-phenylaminopyrimidine class that selectively inhibits the tyrosine kinase activity of the ABL and the platelet-derived growth factor receptor (PDGFR) protein tyrosine kinases. We previously showed that CGP 57148 selectively kills p210BCR-ABL-expressing cells. To extend these observations, we evaluated the ability of CGP 57148 to inhibit other activated ABL tyrosine kinases, including p185BCR-ABL and TEL-ABL. In cell-based assays of ABL tyrosine phosphorylation, inhibition of ABL kinase activity was observed at concentrations similar to that reported for p210BCR-ABL. Consistent with the in vitro profile of this compound, the growth of cells expressing activated ABL protein tyrosine kinases was inhibited in the absence of exogenous growth factor. Growth inhibition was also observed with a p185BCR-ABL-positive acute lymphocytic leukemia (ALL) cell line generated from a Philadelphia chromosome-positive ALL patient. As CGP 57148 inhibits the PDGFR kinase, we also showed that cells expressing an activated PDGFR tyrosine kinase, TEL-PDGFR, are sensitive to this compound. Thus, this compound may be useful for the treatment of a variety of BCR-ABL-positive leukemias and for treatment of the subset of chronic myelomonocytic leukemia patients with a TEL-PDGFR fusion protein.
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INTRODUCTION |
ACTIVATION OF THE ABL oncogene has been associated with a variety of human leukemias. Chronic myelogenous leukemia (CML) is the most common of these with 95% of patients expressing a 210-kD ABL fusion protein in which the first exon of c-ABL has been replaced by BCR sequences encoding 927 or 902 amino acids.1,2 p210BCR-ABL is also present in approximately 5% to 10% of adults with acute leukemia for whom there is no evidence of antecedent CML. Another BCR-ABL fusion protein, p185BCR-ABL, contains only sequences from BCR exon 1 (426 amino acids) fused to exons 2 to 11 of c-ABL and is seen in 5% to 10% of de novo acute lymphocytic leukemias (ALL).3,4
Approximately one third of CML patients are eligible for allogeneic bone marrow transplantation and the cure rate is 70% to 90% for patients who survive the transplant.5,6 For CML patients not eligible for allogeneic bone marrow transplantation, no curative therapy is available, but the average survival is close to 6 years. For patients with BCR-ABL-positive acute leukemias, the prognosis is quite poor. Thus, new therapies are needed for these disorders.
ABL tyrosine kinase activity is required for the transforming function of BCR-ABL proteins.7,8 Sequences from the first exon of BCR are required for activation of the ABL tyrosine kinase and these sequences promote oligomerization of BCR-ABL.9-11 However, sequences other than BCR may be capable of substituting for BCR in activating the transforming ability and tyrosine kinase activity of ABL. An example of this is the TEL gene that encodes a putative transcription factor with homology to the ETS family of DNA binding proteins. An ABL fusion to the TEL gene has been reported in one case of acute myelogenous leukemia (AML), one case of ALL, and a single case of atypical CML.12-14 Fusion of TEL sequences to ABL results in activation of ABL kinase activity and a pattern of cellular tyrosine phosphorylation similar to that induced by BCR-ABL fusion proteins.15
TEL was cloned as a result of its fusion to the intracellular tyrosine kinase domain of the platelet-derived growth factor receptor (PDGFR) in chronic myelomonocytic leukemia (CMML) patients with a 5; 12 chromosome translocation.16 This fusion event results in homodimerization and activation of the PDGFR tyrosine kinase activity.17
We previously reported that the tyrosine kinase inhibitor, CGP 57148, inhibits the ABL and PDGFR tyrosine kinases.18,19 Our data showed that this compound is capable of inhibiting the growth of p210BCR-ABL-or v-ABL-positive cells in vitro and in vivo, but does not inhibit the growth of normal cells or cells transformed by other tyrosine kinases such as v-SRC. To extend these observations, we evaluated the ability of CGP 57148 to inhibit the growth of cells transformed by activated PDGFR or activated ABL tyrosine kinases other than p210BCR-ABL or v-ABL. In this report we show that CGP 57148 has the ability to specifically inhibit the growth of p185BCR-ABL-positive cells, TEL-ABL, and TEL-PDGFR-expressing cells.
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MATERIALS AND METHODS |
Antibodies and Reagents
A stock solution of CGP 57148B at a concentration of 10 mmol/L was prepared by dissolving the compound in sterile phosphate buffered saline (PBS) and was diluted in tissue culture media before use. The antiphosphotyrosine antibody 4G10 was generated using phosphotyramine as the immunogen and was used as described.20 The anti-ABL monoclonal antibody 24-21 was a gift from Naomi Rosenberg, New England Medical Center, Boston, MA and the PDGFR antibody was from UBI (Lake Placid, NY). Other reagents were obtained from Sigma Chemical Co (St Louis, MO) unless otherwise indicated.
Cell Lines
The 32Dcl3 cell line is a murine myeloid cell line that was obtained from Joel Greenberger, University of Massachusetts Medical Center, Worcester, MA.21 BaF3 is a murine progenitor cell line that has characteristics of immature B cells and was obtained from James D. Griffin, Dana Farber Cancer Institute, Boston, MA. Both 32Dcl3 and BaF3 cells are dependent on interleukin-3 (IL-3) for proliferation. Cells were cultured in RPMI 1640 medium (GIBCO, Grand Island, NY) supplemented with 10% fetal bovine serum (FBS; UBI) and 15% WEHI-3B conditioned media as a source of IL-3. MO7e is a human megakaryocytic leukemia cell line that requires either granulocyte-macrophage colony-stimulating factor, IL-3, or stem cell factor (SCF) for proliferation.22
Derivatives of these cell lines expressing p210BCR-ABL, p185BCR-ABL, TEL-ABL, or TEL-PDGFR were created by electroporation with a retrovirus, pGD, containing the respective cDNAs, as described.15,17,23,24 32Dp210, 32Dp185, BaF3 TEL-ABL, and BaF3 TEL-PDGFR cells are factor-independent for proliferation and were grown in RPMI 1640 media supplemented with 10% FBS. K562 cells are a p210BCR-ABL-positive cell line derived from a CML patient in blast crisis.25 A p185BCR-ABL-positive ALL cell line was provided by Fatih Uckin, University of Minnesota.
Proliferation and Differentiation Assays
Cell count assays.
Cells were plated at a density of 2 × 105 cells/mL in RPMI 1640 media with 10% FBS with or without growth factors. Inhibitor was added at various concentrations. Controls using an identical dilution of buffer in which the inhibitor had been dissolved were also performed. Viable cells were counted, as assessed by exclusion of trypan blue, at 24-hour intervals.
MTT assays.
Between 5 × 103 and 2 × 104 cells were plated per well in quadruplicate in RPMI 1640 media with 10% FBS with or without growth factors and various concentrations of inhibitors. Controls were performed using an identical dilution of buffer in which the inhibitor had been dissolved. Wells were assayed for uptake of MTT at daily intervals as described.26 One plate per day contained serial dilutions of cells to ensure that the assay remained linear with respect to the cell concentration used. Results are expressed as the mean optical density (OD).
Immunoblotting Experiments
Inhibition of BCR-ABL, TEL-ABL, and TEL-PDGFR tyrosine kinases.
32Dcl3 or BaF3 cells expressing activated tyrosine kinases were incubated in the presence of various concentrations of inhibitor. After a 1.5-hour incubation, cells were washed twice with PBS and lysed in 1% NP40, 150 mmol/L NaCl, 20 mmol/L Tris pH 7.4, 10% glycerol containing 1 mmol/L phenylmethylsulfonylfluoride, 20 µg/mL aprotinin, and 1 mmol/L sodium orthovanadate at 5 × 107 cells/mL. Equal amounts of lysates (approximately 250 µg) were analyzed by immunoblotting with antiphosphotyrosine or anti-ABL antibodies as described.27 Gels were scanned using a laser densitometer to quantitate the signal intensity.
Inhibition of IL-3-induced tyrosine kinase activity.
32Dcl3 cells were washed twice with RPMI 1640 and resuspended at 2 × 106 cells/mL of RPMI 1640 containing 1% bovine serum albumin. Cells were incubated in this media for 6 to 8 hours. Various concentrations of inhibitor were added for the final 1.5 hours of incubations. At the end of this period, cells were stimulated with 10 ng/mL of murine recombinant IL-3 (UBI). Cells were lysed as described previously and analyzed by antiphosphotyrosine immunoblotting.
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RESULTS |
CGP 57148
CGP 57148 is a compound of the 2-phenylaminopyrimidine class. This class of compounds was designed based on the known structure of the adenosine triphosphate (ATP) binding site of protein kinases. A series of structurally modified congeners of a base compound of this class were produced and analyzed for their ability to inhibit a series of protein kinases. CGP 57148 (Fig 1) was found to be a potent inhibitor of the ABL tyrosine kinase.
A number of other protein kinases were initially examined for inhibition by this compound, including the epidermal growth factor receptor, HER-2/neu, insulin receptor; insulin-like growth factor-1 receptor; PDGFR; c-FGR; c-LCK; c-LYN; c- and v-SRC; and a variety of protein serine/threonine kinases including protein kinase A, phosphorylase kinase, protein kinase C types  ,  1, 2,  ,  ,  ,  , and  , cdc2/cyclin, and casein kinases 1 and 2.18 With the exception of the PDGFR, no inhibitory activity of CGP 57148 was observed at concentrations less than 100 µmol/L.18,19 The PDGFR belongs to a family of receptor tyrosine kinases characterized by five extracellular immunoglobulin-like domains and an interrupted intracellular tyrosine kinase domain. Other members include FMS (CSF-1R), c-KIT, and FLT3. Although CGP 57148 does not inhibit the FLT3 or FMS tyrosine kinases, inhibition of tyrosine phosphorylation induced by stimulation of cells with SCF, the ligand for c-KIT, has been observed (E. Buchdunger, manuscript in preparation).
Inhibition of Protein Tyrosine Kinase Activity In Vitro
Initial studies showed that CGP 57148 was capable of inhibiting substrate phosphorylation by a bacterially expressed v-ABL tyrosine kinase with an IC50 of 0.038 µmol/L,19 where IC50 represents the concentration of compound required to achieve a 50% reduction in the phosphorylation of an exogenous substrate. Additional studies using cell-based assays for inhibition of autophosphorylation by p210BCR-ABL kinase showed an IC50 of 0.25 µmol/L.18 Similar results have been obtained in MO7e cells that express p210BCR-ABL, K562 cells, a p185BCR-ABL ALL cell line, and 32Dcl3 cells expressing p185BCR-ABL. A representative experiment using 32Dcl3 cells expressing p185BCR-ABL is shown in Fig 2. Antiphosphotyrosine and anti-ABL immunoblots were performed on cellular lysates of p185-expressing 32Dcl3 cells incubated for 1.5 hours with various concentrations of inhibitor. No significant differences in the amount of ABL protein were noted on the ABL immunoblot (Fig 2B). However, there was a significant decrease in the amount of phosphotyrosine detected in the presence of CGP 57148 (Fig 2A). Densitometric scans of the BCR-ABL phosphotyrosine band shows that a 50% reduction in the intensity of the phosphotyrosine staining (IC50) of p185BCR-ABL using CGP 57148 occurred at a concentration of 0.25 µmol/L.
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| Fig 2.
IC50 of inhibition of p185BCR-ABL kinase. 32Dp185 cells were incubated for 1.5 hours in the presence of the indicated concentration of inhibitor. Cells were lysed and equal amounts of lysate were analyzed by immunoblotting with antiphosphotyrosine (A) or anti-ABL antibodies (B). The migration of BCR-ABL is marked with an arrow on the left of the panel. These gels were scanned using a laser densitometer. No significant differences in the amount of ABL protein were noted on the ABL immunoblot. The scanned data from the antiphosphotyrosine immunoblot were used to calculate the IC50, defined as a 50% reduction of the intensity of the BCR-ABL phosphotyrosine band. The data shown are representative of two separate experiments and similar values were obtained for the IC50s.
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CGP 57148 also inhibits ligand-stimulated PDGFR tyrosine phosphorylation with an IC50 of 0.3 µmol/L,19 and c-ABL with an IC50 of 0.25 µmol/L suggesting that CGP 57148 is equipotent for inhibition of ABL and PDGFR kinases. Experiments were performed on cell lines expressing TEL-ABL and TEL-PDGFR to determine whether similar effects would be seen in cells expressing ABL or PDGFR activated by other means. These experiments showed an IC50 of 0.35 µmol/L for TEL-ABL and 0.15 for TEL-PDGFR (Fig 3), suggesting that the mechanism of activation of these kinases did not alter the ability of CGP 57148 to inhibit their activity.
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| Fig 3.
IC50 of inhibition of TEL-ABL and TEL-PDGFR kinases. BaF3 TEL-ABL (A) or BAF3 TEL-PDGFR (B) cells were incubated for 1.5 hours in the presence of the indicated concentration of inhibitor. Cells were lysed and equal amounts of lysate were analyzed by immunoblotting with antiphosphotyrosine (top panel of A and B) or anti-ABL or anti-PDGFR antibodies (bottom panel of A and B). Data were analyzed as for Fig 2. The data shown are representative of two separate experiments and similar values were obtained for the IC50s.
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Cell Proliferation Assays
To determine whether inhibition of the ABL or PDGFR kinases would have any effects on the cells expressing these kinases, cell proliferation assays were performed. Preliminary studies with CGP 57148 were performed with concentrations of CGP 57148 ranging from 0.01 µmol/L to 100 µmol/L. No toxicity against parental BaF3, 32Dcl3, or MO7e cells was seen at doses up to 10 µmol/L (Fig 4). However, at 100 µmol/L CGP 57148, these cells were killed. 32Dcl3 and BaF3 cells are absolutely dependent on the presence of exogenous IL-3 for survival and proliferation. Because IL-3 signal transduction is known to activate a number of tyrosine kinases, including JAK-2,28 we examined antiphosphotyrosine immunoblots of BaF3 or 32Dcl3 cells stimulated with IL-3 in the presence or absence of CGP 57148. No inhibition of tyrosine phosphorylation was seen even at concentrations of CGP 57148 of 100 µmol/L, at which cell death was observed (data not shown).
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| Fig 4.
Dose response of inhibition of growth of 32Dcl3 cells. 32Dcl3 cells were incubated in quadruplicate in the presence of regular growth media with the indicated amount of inhibitor. Wells were assayed for uptake of MTT at daily intervals. The data shown are representative of three separate experiments. Similar results have been obtained using MO7e and BaF3 cells.
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We previously showed that CGP 57148 inhibited the growth of 32Dcl3 and MO7e cells expressing p210BCR-ABL at concentrations of 1 or 10 µmol/L.18 To extend these observations, we tested cell lines that expressed p185BCR-ABL, TEL-ABL, and TEL-PDGF. CGP 57148 at 1 or 10 µmol/L killed cells expressing these constructs in the absence of exogenous growth factor (Fig 5). This included a p185BCR-ABL-positive ALL cell line generated from a Philadelphia chromosome-positive ALL patient (data not shown). However, 32Dcl3 cells expressing p185BCR-ABL and BaF3 cells expressing TEL-ABL or TEL-PDGFR were rescued by the addition of IL-3 (Fig 5). This is consistent with our data for another murine cell 32Dp210. However, a human cell line, MO7p210, cannot be rescued by the addition of growth factors normally required for cellular proliferation.18
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| Fig 5.
Cell proliferation assays. (A) 32Dp185 cells were plated in quadruplicate in the presence of regular growth media with or without IL-3 and the indicated amount of inhibitor. Wells were assayed for uptake of MTT at daily intervals. Results are expressed as the mean OD. These assays have been performed four times, all with similar results. (B through D) Cells were plated in the presence of regular growth media with or without IL-3 and the indicated amount of inhibitor. Each day, viable cells were counted as assessed by exclusion of trypan blue. (B) BaF3 cells, (C) BaF3 TEL-ABL cells, (D) BaF3 TEL-PDGFR cells. The data shown are representative of three separate experiments.
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DISCUSSION |
CGP 57148 is a tyrosine kinase inhibitor that shows specificity at the submicromolar level for the ABL and PDGFR kinases. This compound was designed based on the structure of the ATP binding site of protein kinases. Given the high degree of conservation of protein kinases in this region, it is a bit surprising to see selective inhibition of the ABL and PDGFR tyrosine kinases by this compound. Therefore, this specificity may reflect subtle differences in the structure of the protein kinases, even in this highly conserved region. It is also of interest that this compound inhibits the two tyrosine kinases that have been associated with proliferative hematologic malignancies.
We previously showed that CGP 57148 selectively kills p210BCR-ABL-expressing cells.18 This includes K562 cells and MO7e and 32Dcl3 cells engineered to express p210BCR-ABL. No effects of this compound, CGP 57148, were observed using 32Dv-SRC cells or parental cells, 32Dcl3, and MO7e. These observations have been extended to include other activated versions of ABL, such as p185BCR-ABL and TEL-ABL. The IC50 for inhibition of these activated versions of ABL is similar to that observed for c-ABL and BCR-ABL. In assays of substrate phosphorylation, the IC50 for ABL using CGP 57148 was 0.038 µmol/L and in cell-based assays of autophosphorylation the IC50 was 0.25 to 0.35 µmol/L. For cell killing, the concentration of compound required was 1 µmol/L with little or no effect observed at 0.1 µmol/L. This range of concentrations likely reflects the difference in the endpoint used for the assay. Thus, phosphorylation of an exogenous substrate is more readily inhibited than autophosphorylation. These data also suggest that greater than 50% of the tyrosine kinase activity of BCR-ABL must be suppressed for inhibition of cellular proliferation.
Consistent with the in vitro profile of this compound, the growth of cells expressing these activated ABL protein tyrosine kinases was inhibited in the absence of exogenous growth factor. This suggests that these cells are dependent on the activated ABL protein tyrosine kinase for proliferation and/or survival. This also suggests that inhibition of the ABL kinase occurs regardless of the mechanism of activation or that TEL and BCR activate ABL in a similar fashion. As these cells can be rescued by the addition of exogenous growth factor, our data are consistent with BCR-ABL activation of a signaling pathway that overlaps growth factor-activated pathways. These data also suggest that cells expressing an activated ABL or PDGFR could be resistant to the effects of CGP 57148 if other pathways for survival or proliferation are activated by genetic changes in addition to BCR-ABL or a TEL fusion.
Nonspecific toxicity of CGP 57148 was observed at concentrations of 100 µmol/L. The term nonspecific toxicity is used because we have not observed inhibition of cellular tyrosine phosphorylation at these concentrations and because BCR-ABL-expressing cells are killed at concentrations of 1 µmol/L of CGP 57148. Of course, it is possible that inhibition of tyrosine kinases at these higher concentrations does occur but is not detected by immunoblotting. It is also possible that, at higher concentrations, other ATP-dependent reactions could be inhibited or that other unknown processes are affected.
As CGP 57148 inhibits the PDGFR kinase, we also showed that cells expressing an activated PDGFR tyrosine kinase, TEL-PDGFR, are sensitive to this compound. Thus, this compound may be useful for the treatment of a variety of BCR-ABL-positive leukemias and for treatment of the subset of CMML patients with a TEL-PDGFR fusion protein.
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FOOTNOTES |
Submitted April 15, 1997;
accepted August 14, 1997.
Supported in part by Grant No. CA01422 (B.J.D.) and Novartis Pharma. B.J.D. and D.G.G. are recipients of Translational Research Awards from the Leukemia Society of America.
Address reprint requests to Brian J. Druker, MD, Division of Hematology and Medical Oncology, L592, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201-3098.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hearly marked
``advertisment'' in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
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REFERENCES |
1.
Ben-Neriah Y,
Daley GQ,
Mes-Masson A-M,
Witte ON,
Baltimore D:
The chronic myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrid gene.
Science
233:212,
1986
2.
Shtivelman E,
Lifshitz B,
Gale RP,
Canaani E:
Fused transcript of abl and bcr genes in chronic myelogenous leukaemia.
Nature
315:550,
1985
3.
Hermans A,
Heisterkamp N,
von Lindern M,
van Baal S,
Meijer D,
van der Plas D,
Wiedemann LM,
Groffen J,
Bootsma D,
Grosveld G:
Unique fusion of bcr and c-abl genes in Philadelphia chromosome positive acute lymphoblastic leukemia.
Cell
51:33,
1987
4.
Clark SS,
McLaughlin J,
Timmons M,
Pendergast AM,
Ben-Neriah Y,
Dow LW,
Crist W,
Rovera G,
Smith SD,
Witte ON:
Expression of a distinctive BCR-ABL oncogene in Ph1-positive acute lymphocytic leukemia (ALL).
Science
239:775,
1988
5.
Kantarjian HM,
Deisseroth AB,
Kurzrock R,
Estrov Z,
Talpaz M:
Chronic myelogenous leukemia: A concise update.
Blood
82:691,
1993
6.
Goldman JM:
Management of chronic myeloid leukaemia.
Blood Rev
8:21,
1994
7.
Lugo TG,
Pendergast AM,
Muller AJ,
Witte ON:
Tyrosine kinase activity and transformation potency of bcr-abl oncogene products.
Science
247:1079,
1990
8.
Oda T,
Tamura S,
Matsuguchi T,
Griffin JD,
Druker BJ:
The SH2 domain of Abl is not required for factor independent growth induced by Bcr-Abl in a murine myeloid cell line.
Leukemia
9:295,
1995
9.
McWhirter JR,
Wang JYJ:
Activation of tyrosine kinase and microfilament-binding functions of c-abl by bcr sequences in bcr/abl fusion proteins.
Mol Cell Biol
11:1553,
1991
10.
McWhirter JR,
Galasso DL,
Wang JYJ:
A coiled-coiled oligomerization domain of Bcr is essential for the transforming function of Bcr-ABl oncoproteins.
Mol Cell Biol
13:7587,
1993
11.
Muller AJ,
Young JC,
Pendergast AM,
Pondel M,
Landau NR,
Littman DR,
Witte ON:
BCR first exon sequences specifically activate the BCR/ABL tyrosine kinase oncogene of Philadelphia chromosome-positive human leukemias.
Mol Cell Biol
11:1785,
1991
12.
Papadopoulos P,
Ridge SA,
Boucher CA,
Stocking C,
Wiedemann LM:
The novel activation of ABL by fusion to an ets-related gene, TEL.
Cancer Res
55:34,
1995
13. Golub TR, McLean T, Stegmaier K, Carroll M, Tomasson M, Gilliland DG: The TEL gene and human leukemia. Biochimica et Biophysica Acta 1288:M7, 1996
14.
Golub TR,
Goga A,
Barker GF,
Afar DE,
McLaughlin J,
Bohlander SK,
Rowley JD,
Witte ON,
Gilliland DG:
Oligomerization of the ABL tyrosine kinase by the Ets protein TEL in human leukemia.
Mol Cell Biol
16:4107,
1996
15.
Okuda K,
Golub TR,
Gilliland DG,
Griffin JD:
p210BCR/ABL, p190BCR/ABL, and TEL/ABL activate similar signal transduction pathways in hematopoietic cells.
Oncogene
13:1147,
1996
16.
Golub TR,
Barker GF,
Lovett M,
Gilliland DG:
Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5; 12) chromosomal translocation.
Cell
77:307,
1994
17.
Carroll M,
Tomasson MH,
Barker GF,
Golub TR,
Gilliland DG:
The Tel platelet-derived growth factor beta receptor (PDGF-beta-R) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGF-beta-R kinase-dependent signaling pathways.
Proc Natl Acad Sci USA
93:14845,
1996
18.
Druker BJ,
Tamura S,
Buchdunger E,
Ohno S,
Segal GM,
Fanning S,
Zimmermann J,
Lydon NB:
Effects of a selective inhibitor of the ABL tyrosine kinase on the growth of BCR-ABL positive cells.
Nature Med
2:561,
1996
19.
Buchdunger E,
Zimmermann J,
Mett H,
Meyer T,
Müller M,
Druker BJ,
Lydon NB:
Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative.
Cancer Res
56:100,
1996
20.
Kanakura Y,
Druker B,
Cannistra SA,
Furukawa Y,
Torimoto Y,
Griffin JD:
Signal transduction of the human granulocyte-macrophage colony-stimulating factor and interleukin-3 receptors involves a common set of cytoplasmic proteins.
Blood
76:706,
1990
21.
Greenberger JS,
Sakakeeny MA,
Humphries RK,
Eaves CJ,
Eckner RJ:
Demonstration of permanent factor-dependent multipotential (erythroid/neutrophil/basophil) hematopoietic progenitor cell lines.
Proc Natl Acad Sci USA
80:2391,
1983
22.
Avanzi GC,
Lista P,
Giovinazzo B,
Miniero R,
Saglio G,
Benetton G,
Coda R,
Cattoretti G,
Pegoraro L:
Selective growth response to IL-3 of a human leukaemic cell line with megakaryoblastic features.
Br J Haematol
69:359,
1988
23.
Matsuguchi T,
Salgia R,
Hallek M,
Eder M,
Druker B,
Ernst T,
Griffin JD:
SHC phosphorylation in myeloid cells is regulated by GM-CSF, IL-3, and steel factor and is constitutively increased by p210BCR-ABL.
J Biol Chem
269:5016,
1994
24.
Matulonis U,
Salgia R,
Okuda K,
Druker B,
Griffin JD:
IL-3 and p210BCR/ABL activate both unique and overlapping pathways of signal transduction in a factor-dependent myeloid cell line.
Exp Hematol
21:1460,
1993
25.
Lozzio CB,
Lozzio BB:
Human chronic myelogenous leukemia cell line with positive Philadelphia chromosome.
Blood
45:321,
1975
26.
Mossman T:
Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays.
J Immunol Methods
65:55,
1983
27.
Druker B,
Okuda K,
Matulonis U,
Salgia R,
Roberts T,
Griffin JD:
Tyrosine phosphorylation of rasGAP and associated proteins in chronic myelogenous leukemia cell lines.
Blood
79:2215,
1992
28.
Silvennoinen O,
Witthuhn BA,
Quelle FW,
Cleveland JL,
Yi T,
Ihle JN:
Structure of the murine Jak2 protein-tyrosine kinase and its role in interleukin 3 signal transduction.
Proc Natl Acad Sci USA
90:8429,
1993
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|
B. J. Druker
Translation of the Philadelphia chromosome into therapy for CML
Blood,
December 15, 2008;
112(13):
4808 - 4817.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Larmonier, N. Janikashvili, C. J. LaCasse, C. B. Larmonier, J. Cantrell, E. Situ, T. Lundeen, B. Bonnotte, and E. Katsanis
Imatinib Mesylate Inhibits CD4+CD25+ Regulatory T Cell Activity and Enhances Active Immunotherapy against BCR-ABL- Tumors
J. Immunol.,
November 15, 2008;
181(10):
6955 - 6963.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. F. Tam, T.-L. Gu, J. Chen, B. H. Lee, L. Bullinger, S. Frohling, A. Wang, S. Monti, T. R. Golub, and D. G. Gilliland
Id1 is a common downstream target of oncogenic tyrosine kinases in leukemic cells
Blood,
September 1, 2008;
112(5):
1981 - 1992.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. J. Schilder, M. W. Sill, R. B. Lee, T. J. Shaw, M. K. Senterman, A. J. Klein-Szanto, Z. Miner, and B. C. Vanderhyden
Phase II Evaluation of Imatinib Mesylate in the Treatment of Recurrent or Persistent Epithelial Ovarian or Primary Peritoneal Carcinoma: A Gynecologic Oncology Group Study
J. Clin. Oncol.,
July 10, 2008;
26(20):
3418 - 3425.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Andrae, R. Gallini, and C. Betsholtz
Role of platelet-derived growth factors in physiology and medicine
Genes & Dev.,
May 15, 2008;
22(10):
1276 - 1312.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. V. Sharma and J. Settleman
Oncogene addiction: setting the stage for molecularly targeted cancer therapy
Genes & Dev.,
December 15, 2007;
21(24):
3214 - 3231.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Ali, Y. Lin, M. M. Gharibo, M. K. Gounder, M. N. Stein, T. F. Lagattuta, M. J. Egorin, E. H. Rubin, and E. A. Poplin
Phase I and Pharmacokinetic Study of Imatinib Mesylate (Gleevec) and Gemcitabine in Patients with Refractory Solid Tumors
Clin. Cancer Res.,
October 1, 2007;
13(19):
5876 - 5882.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Baccarani, D. Cilloni, M. Rondoni, E. Ottaviani, F. Messa, S. Merante, M. Tiribelli, F. Buccisano, N. Testoni, E. Gottardi, et al.
The efficacy of imatinib mesylate in patients with FIP1L1-PDGFR{alpha}-positive hypereosinophilic syndrome. Results of a multicenter prospective study
Haematologica,
September 1, 2007;
92(9):
1173 - 1179.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Kinoshita-Kikuta, Y. Aoki, E. Kinoshita, and T. Koike
Label-free Kinase Profiling Using Phosphate Affinity Polyacrylamide Gel Electrophoresis
Mol. Cell. Proteomics,
February 1, 2007;
6(2):
356 - 366.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. David, N. C. P. Cross, S. Burgstaller, A. Chase, C. Curtis, R. Dang, M. Gardembas, J. M. Goldman, F. Grand, G. Hughes, et al.
Durable responses to imatinib in patients with PDGFRB fusion gene-positive and BCR-ABL-negative chronic myeloproliferative disorders
Blood,
January 1, 2007;
109(1):
61 - 64.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Z. Carter, D. H. Mak, W. D. Schober, M. Cabreira-Hansen, M. Beran, T. McQueen, W. Chen, and M. Andreeff
Regulation of survivin expression through Bcr-Abl/MAPK cascade: targeting survivin overcomes imatinib resistance and increases imatinib sensitivity in imatinib-responsive CML cells
Blood,
February 15, 2006;
107(4):
1555 - 1563.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. B. Hickey and T. G. Cotter
BCR-ABL Regulates Phosphatidylinositol 3-Kinase-p110{gamma} Transcription and Activation and Is Required for Proliferation and Drug Resistance
J. Biol. Chem.,
February 3, 2006;
281(5):
2441 - 2450.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. B. Hickey, K. England, and T. G. Cotter
Bcr-Abl regulates osteopontin transcription via Ras, PI-3K, aPKC, Raf-1, and MEK
J. Leukoc. Biol.,
July 1, 2005;
78(1):
289 - 300.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Yoshiji, R. Noguchi, S. Kuriyama, Y. Ikenaka, J. Yoshii, K. Yanase, T. Namisaki, M. Kitade, T. Masaki, and H. Fukui
Imatinib mesylate (STI-571) attenuates liver fibrosis development in rats
Am J Physiol Gastrointest Liver Physiol,
May 1, 2005;
288(5):
G907 - G913.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. L. Dewar, A. C. Cambareri, A. C. W. Zannettino, B. L. Miller, K. V. Doherty, T. P. Hughes, and A. B. Lyons
Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib
Blood,
April 15, 2005;
105(8):
3127 - 3132.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Deininger, E. Buchdunger, and B. J. Druker
The development of imatinib as a therapeutic agent for chronic myeloid leukemia
Blood,
April 1, 2005;
105(7):
2640 - 2653.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Appel, A. Rupf, M. M. Weck, O. Schoor, T. H. Brummendorf, T. Weinschenk, F. Grunebach, and P. Brossart
Effects of Imatinib on Monocyte-Derived Dendritic Cells Are Mediated by Inhibition of Nuclear Factor-{kappa}B and Akt Signaling Pathways
Clin. Cancer Res.,
March 1, 2005;
11(5):
1928 - 1940.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. D. Unwin, D. W. Sternberg, Y. Lu, A. Pierce, D. G. Gilliland, and A. D. Whetton
Global Effects of BCR/ABL and TEL/PDGFR{beta} Expression on the Proteome and Phosphoproteome: IDENTIFICATION OF THE RHO PATHWAY AS A TARGET OF BCR/ABL
J. Biol. Chem.,
February 25, 2005;
280(8):
6316 - 6326.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Wang, F. Cheng, A. Cuenca, P. Horna, Z. Zheng, K. Bhalla, and E. M. Sotomayor
Imatinib mesylate (STI-571) enhances antigen-presenting cell function and overcomes tumor-induced CD4+ T-cell tolerance
Blood,
February 1, 2005;
105(3):
1135 - 1143.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Tefferi
Blood Eosinophilia: A New Paradigm in Disease Classification, Diagnosis, and Treatment
Mayo Clin. Proc.,
January 1, 2005;
80(1):
75 - 83.
[Abstract]
[PDF]
|
|
|
|
|
|
|
M. Wadleigh, D. J. DeAngelo, J. D. Griffin, and R. M. Stone
After chronic myelogenous leukemia: tyrosine kinase inhibitors in other hematologic malignancies
Blood,
January 1, 2005;
105(1):
22 - 30.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. B. Jones, H. Y. Lu, and Q. Lu
Abl Tyrosine Kinase Promotes Dendrogenesis by Inducing Actin Cytoskeletal Rearrangements in Cooperation with Rho Family Small GTPases in Hippocampal Neurons
J. Neurosci.,
September 29, 2004;
24(39):
8510 - 8521.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Potula, N. Dhillion, Y. Sui, C. A. Zien, K. Funa, D. Pinson, M. S. Mayo, D. K. Singh, O. Narayan, and S. Buch
Association of Platelet-Derived Growth Factor-B Chain with Simian Human Immunodeficiency Virus Encephalitis
Am. J. Pathol.,
September 1, 2004;
165(3):
815 - 824.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. B. Dietz, L. Souan, G. J. Knutson, P. A. Bulur, M. R. Litzow, and S. Vuk-Pavlovic
Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo
Blood,
August 15, 2004;
104(4):
1094 - 1099.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Lefevre, A.-L. Glotin, A. Calipel, F. Mouriaux, T. Tran, Z. Kherrouche, C.-A. Maurage, C. Auclair, and F. Mascarelli
Roles of Stem Cell Factor/c-Kit and Effects of Glivec(R)/STI571 in Human Uveal Melanoma Cell Tumorigenesis
J. Biol. Chem.,
July 23, 2004;
279(30):
31769 - 31779.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. P. Million, N. Harakawa, S. Roumiantsev, L. Varticovski, and R. A. Van Etten
A Direct Binding Site for Grb2 Contributes to Transformation and Leukemogenesis by the Tel-Abl (ETV6-Abl) Tyrosine Kinase
Mol. Cell. Biol.,
June 1, 2004;
24(11):
4685 - 4695.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Rosti, G. Martinelli, S. Bassi, M. Amabile, E. Trabacchi, B. Giannini, D. Cilloni, B. Izzo, A. De Vivo, N. Testoni, et al.
Molecular response to imatinib in late chronic-phase chronic myeloid leukemia
Blood,
March 15, 2004;
103(6):
2284 - 2290.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Matei, D. D. Chang, and M.-H. Jeng
Imatinib Mesylate (Gleevec) Inhibits Ovarian Cancer Cell Growth through a Mechanism Dependent on Platelet-Derived Growth Factor Receptor {alpha} and Akt Inactivation
Clin. Cancer Res.,
January 15, 2004;
10(2):
681 - 690.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Appel, A. M. Boehmler, F. Grunebach, M. R. Muller, A. Rupf, M. M. Weck, U. Hartmann, V. L. Reichardt, L. Kanz, T. H. Brummendorf, et al.
Imatinib mesylate affects the development and function of dendritic cells generated from CD34+ peripheral blood progenitor cells
Blood,
January 15, 2004;
103(2):
538 - 544.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. T. Ferrao, M. J. Frost, S.-P. Siah, and L. K. Ashman
Overexpression of P-glycoprotein in K562 cells does not confer resistance to the growth inhibitory effects of imatinib (STI571) in vitro
Blood,
December 15, 2003;
102(13):
4499 - 4503.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Vlahovic and J. Crawford
Activation of Tyrosine Kinases in Cancer
Oncologist,
December 1, 2003;
8(6):
531 - 538.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Grunberger, P. Demin, O. Rounova, N. Sharfe, L. Cimpean, H. Dadi, A. Freywald, Z. Estrov, and C. M. Roifman
Inhibition of acute lymphoblastic and myeloid leukemias by a novel kinase inhibitor
Blood,
December 1, 2003;
102(12):
4153 - 4158.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Pfeifer, B. Wassmann, W.-K. Hofmann, M. Komor, U. Scheuring, P. Bruck, A. Binckebanck, E. Schleyer, N. Gokbuget, T. Wolff, et al.
Risk and Prognosis of Central Nervous System Leukemia in Patients with Philadelphia Chromosome-Positive Acute Leukemias Treated with Imatinib Mesylate
Clin. Cancer Res.,
October 15, 2003;
9(13):
4674 - 4681.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. W. N. Deininger and B. J. Druker
Specific Targeted Therapy of Chronic Myelogenous Leukemia with Imatinib
Pharmacol. Rev.,
September 1, 2003;
55(3):
401 - 423.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. H. Antin
A 41-Year-Old Woman With Chronic Myelogenous Leukemia
JAMA,
August 27, 2003;
290(8):
1083 - 1090.
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Wheadon and M. J. Welham
The coupling of TEL/PDGF{beta}R to distinct functional responses is modulated by the presence of cytokine: involvement of mitogen-activated protein kinases
Blood,
August 15, 2003;
102(4):
1480 - 1489.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Yu, M. Rahmani, J. Almenara, M. Subler, G. Krystal, D. Conrad, L. Varticovski, P. Dent, and S. Grant
Histone Deacetylase Inhibitors Promote STI571-mediated Apoptosis in STI571-sensitive and -resistant Bcr/Abl+ Human Myeloid Leukemia Cells
Cancer Res.,
May 1, 2003;
63(9):
2118 - 2126.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. J. Abrams, L. B. Lee, L. J. Murray, N. K. Pryer, and J. M. Cherrington
SU11248 Inhibits KIT and Platelet-derived Growth Factor Receptor {beta} in Preclinical Models of Human Small Cell Lung Cancer
Mol. Cancer Ther.,
May 1, 2003;
2(5):
471 - 478.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. G. Chiorean, S. J. Dylla, K. Olsen, T. Lenvik, Y. Soignier, and J. S. Miller
BCR/ABL alters the function of NK cells and the acquisition of killer immunoglobulin-like receptors (KIRs)
Blood,
May 1, 2003;
101(9):
3527 - 3533.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Benekli, M. R. Baer, H. Baumann, and M. Wetzler
Signal transducer and activator of transcription proteins in leukemias
Blood,
April 15, 2003;
101(8):
2940 - 2954.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Cools, D. J. DeAngelo, J. Gotlib, E. H. Stover, R. D. Legare, J. Cortes, J. Kutok, J. Clark, I. Galinsky, J. D. Griffin, et al.
A Tyrosine Kinase Created by Fusion of the PDGFRA and FIP1L1 Genes as a Therapeutic Target of Imatinib in Idiopathic Hypereosinophilic Syndrome
N. Engl. J. Med.,
March 27, 2003;
348(13):
1201 - 1214.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Uehara, S. J. Kim, T. Karashima, D. L. Shepherd, D. Fan, R. Tsan, J. J. Killion, C. Logothetis, P. Mathew, and I. J. Fidler
Effects of Blocking Platelet-Derived Growth Factor-Receptor Signaling in a Mouse Model of Experimental Prostate Cancer Bone Metastases
J Natl Cancer Inst,
March 19, 2003;
95(6):
458 - 470.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Hole and D. Blake
A review of imatinib mesilate in the treatment of patients with gastrointestinal stromal tumours and chronic myeloid leukaemia
Journal of Oncology Pharmacy Practice,
March 1, 2003;
9(1):
1 - 14.
[Abstract]
[PDF]
|
|
|
|
|
|
|
S. Kumar, N. Mishra, D. Raina, S. Saxena, and D. Kufe
Abrogation of the Cell Death Response to Oxidative Stress by the c-Abl Tyrosine Kinase Inhibitor STI571
Mol. Pharmacol.,
February 1, 2003;
63(2):
276 - 282.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Golas, K. Arndt, C. Etienne, J. Lucas, D. Nardin, J. Gibbons, P. Frost, F. Ye, D. H. Boschelli, and F. Boschelli
SKI-606, a 4-Anilino-3-quinolinecarbonitrile Dual Inhibitor of Src and Abl Kinases, Is a Potent Antiproliferative Agent against Chronic Myelogenous Leukemia Cells in Culture and Causes Regression of K562 Xenografts in Nude Mice
Cancer Res.,
January 15, 2003;
63(2):
375 - 381.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. C. McGary, K. Weber, L. Mills, M. Doucet, V. Lewis, D. C. Lev, I. J. Fidler, and M. Bar-Eli
Inhibition of Platelet-derived Growth Factor-mediated Proliferation of Osteosarcoma Cells by the Novel Tyrosine Kinase Inhibitor STI571
Clin. Cancer Res.,
November 1, 2002;
8(11):
3584 - 3591.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Kozaki, W. E. Kaminski, J. Tang, S. Hollenbach, P. Lindahl, C. Sullivan, J.-C. Yu, K. Abe, P. J. Martin, R. Ross, et al.
Blockade of Platelet-Derived Growth Factor or Its Receptors Transiently Delays but Does Not Prevent Fibrous Cap Formation in ApoE Null Mice
Am. J. Pathol.,
October 1, 2002;
161(4):
1395 - 1407.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Frost, P. T. Ferrao, T. P. Hughes, and L. K. Ashman
Juxtamembrane Mutant V560GKit Is More Sensitive to Imatinib (STI571) Compared with Wild-Type c-Kit Whereas the Kinase Domain Mutant D816VKit Is Resistant
Mol. Cancer Ther.,
October 1, 2002;
1(12):
1115 - 1124.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Yu, G. Krystal, P. Dent, and S. Grant
Flavopiridol Potentiates STI571-induced Mitochondrial Damage and Apoptosis in BCR-ABL-positive Human Leukemia Cells
Clin. Cancer Res.,
September 1, 2002;
8(9):
2976 - 2984.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. F. Apperley, M. Gardembas, J. V. Melo, R. Russell-Jones, B. J. Bain, E. J. Baxter, A. Chase, J. M. Chessells, M. Colombat, C. E. Dearden, et al.
Response to Imatinib Mesylate in Patients with Chronic Myeloproliferative Diseases with Rearrangements of the Platelet-Derived Growth Factor Receptor Beta
N. Engl. J. Med.,
August 15, 2002;
347(7):
481 - 487.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. K. Magnusson, K. E. Meade, R. Nakamura, J. Barrett, and C. E. Dunbar
Activity of STI571 in chronic myelomonocytic leukemia with a platelet-derived growth factor beta receptor fusion oncogene
Blood,
July 18, 2002;
100(3):
1088 - 1091.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. J. Baxter, A. Hochhaus, P. Bolufer, A. Reiter, J. M. Fernandez, L. Senent, J. Cervera, F. Moscardo, M. A. Sanz, and N. C.P. Cross
The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA
Hum. Mol. Genet.,
June 1, 2002;
11(12):
1391 - 1397.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Raina, N. Mishra, S. Kumar, S. Kharbanda, S. Saxena, and D. Kufe
Inhibition of c-Abl with STI571 Attenuates Stress-Activated Protein Kinase Activation and Apoptosis in the Cellular Response to 1-beta -D-Arabinofuranosylcytosine
Mol. Pharmacol.,
June 1, 2002;
61(6):
1489 - 1495.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. P. Million, J. Aster, D. G. Gilliland, and R. A. Van Etten
The Tel-Abl (ETV6-Abl) tyrosine kinase, product of complex (9;12) translocations in human leukemia, induces distinct myeloproliferative disease in mice
Blood,
May 29, 2002;
99(12):
4568 - 4577.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. B. Dash, I. R. Williams, J. L. Kutok, M. H. Tomasson, E. Anastasiadou, K. Lindahl, S. Li, R. A. Van Etten, J. Borrow, D. Housman, et al.
A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9
PNAS,
May 28, 2002;
99(11):
7622 - 7627.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. S. Holtz, M. L. Slovak, F. Zhang, C. L. Sawyers, S. J. Forman, and R. Bhatia
Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation
Blood,
May 15, 2002;
99(10):
3792 - 3800.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. G. O'Brien, S. A. D. Vieira, S. Connors, N. Bown, J. Chang, R. Capdeville, and J. V. Melo
Transient response to imatinib mesylate (STI571) in a patient with the ETV6-ABL t(9;12) translocation
Blood,
May 1, 2002;
99(9):
3465 - 3467.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Dierov, Q. Xu, R. Dierova, and M. Carroll
TEL/platelet-derived growth factor receptor beta activates phosphatidylinositol 3 (PI3) kinase and requires PI3 kinase to regulate the cell cycle
Blood,
March 1, 2002;
99(5):
1758 - 1765.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. G. Savage and K. H. Antman
Imatinib Mesylate -- A New Oral Targeted Therapy
N. Engl. J. Med.,
February 28, 2002;
346(9):
683 - 693.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Mauro, M. O'Dwyer, M. C. Heinrich, and B. J. Druker
STI571: A Paradigm of New Agents for Cancer Therapeutics
J. Clin. Oncol.,
January 1, 2002;
20(1):
325 - 334.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Kelly, Q. Liu, J. L. Kutok, I. R. Williams, C. L. Boulton, and D. G. Gilliland
FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model
Blood,
January 1, 2002;
99(1):
310 - 318.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. W. Sternberg, M. H. Tomasson, M. Carroll, D. P. Curley, G. Barker, M. Caprio, A. Wilbanks, A. Kazlauskas, and D. G. Gilliland
The TEL/PDGFbeta R fusion in chronic myelomonocytic leukemia signals through STAT5-dependent and STAT5-independent pathways
Blood,
December 1, 2001;
98(12):
3390 - 3397.
[Abstract]
[Full Text]
[PDF]
|
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|
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N. C. Wolff and R. L. Ilaria Jr
Establishment of a murine model for therapy-treated chronic myelogenous leukemia using the tyrosine kinase inhibitor STI571
Blood,
November 1, 2001;
98(9):
2808 - 2816.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-C. Yu, N. A. Lokker, S. Hollenbach, M. Apatira, J. Li, A. Betz, D. Sedlock, S. Oda, Y. Nomoto, K. Matsuno, et al.
Efficacy of the Novel Selective Platelet-Derived Growth Factor Receptor Antagonist CT52923 on Cellular Proliferation, Migration, and Suppression of Neointima following Vascular Injury
J. Pharmacol. Exp. Ther.,
September 1, 2001;
298(3):
1172 - 1178.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Sjoblom, A. Shimizu, K. P. O'Brien, K. Pietras, P. Dal Cin, E. Buchdunger, J. P. Dumanski, A. Ostman, and C.-H. Heldin
Growth Inhibition of Dermatofibrosarcoma Protuberans Tumors by the Platelet-derived Growth Factor Receptor Antagonist STI571 through Induction of Apoptosis
Cancer Res.,
August 1, 2001;
61(15):
5778 - 5783.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
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M. Gianni', Y. Kalac, I. Ponzanelli, A. Rambaldi, M. Terao, and E. Garattini
Tyrosine kinase inhibitor STI571 potentiates the pharmacologic activity of retinoic acid in acute promyelocytic leukemia cells: effects on the degradation of RAR{alpha} and PML-RAR{alpha}
Blood,
May 15, 2001;
97(10):
3234 - 3243.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
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N. J. Donato, J. Y. Wu, L. Zhang, H. Kantarjian, and M. Talpaz
Down-regulation of interleukin-3/granulocyte-macrophage colony-stimulating factor receptor {beta}-chain in BCR-ABL+ human leukemic cells: association with loss of cytokine-mediated Stat-5 activation and protection from apoptosis after BCR-ABL inhibition
Blood,
May 1, 2001;
97(9):
2846 - 2853.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
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K. Okuda, E. Weisberg, D. G. Gilliland, and J. D. Griffin
ARG tyrosine kinase activity is inhibited by STI571
Blood,
April 15, 2001;
97(8):
2440 - 2448.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Sun, J. E. Layton, A. Elefanty, and G. J. Lieschke
Comparison of effects of the tyrosine kinase inhibitors AG957, AG490, and STI571 on BCR-ABL-expressing cells, demonstrating synergy between AG490 and STI571
Blood,
April 1, 2001;
97(7):
2008 - 2015.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. L. Matheson, J. McNamee, and B. J. Jean-Claude
Design of a Chimeric 3-Methyl-1,2,3-triazene with Mixed Receptor Tyrosine Kinase and DNA Damaging Properties: A Novel Tumor Targeting Strategy
J. Pharmacol. Exp. Ther.,
March 1, 2001;
296(3):
832 - 840.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
P. A. Tilbrook, G. A. Palmer, T. Bittorf, D. J. McCarthy, M. J. Wright, M. K. Sarna, D. Linnekin, V. S. Cull, J. H. Williams, E. Ingley, et al.
Maturation of Erythroid Cells and Erythroleukemia Development Are Affected by the Kinase Activity of Lyn
Cancer Res.,
March 1, 2001;
61(6):
2453 - 2458.
[Abstract]
[Full Text]
|
|
|
|
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|
N. Uemura and J. D. Griffin
The ABL kinase inhibitor STI571 does not affect survival of hematopoietic cells after ionizing radiation
Blood,
November 1, 2000;
96(9):
3294 - 3295.
[Full Text]
[PDF]
|
|
|
|
|
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|
E. Buchdunger, C. L. Cioffi, N. Law, D. Stover, S. Ohno-Jones, B. J. Druker, and N. B. Lydon
Abl Protein-Tyrosine Kinase Inhibitor STI571 Inhibits In Vitro Signal Transduction Mediated by c-Kit and Platelet-Derived Growth Factor Receptors
J. Pharmacol. Exp. Ther.,
October 1, 2000;
295(1):
139 - 145.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
F. Gesbert and J. D. Griffin
Bcr/Abl activates transcription of the Bcl-X gene through STAT5
Blood,
September 15, 2000;
96(6):
2269 - 2276.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
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G. W. Krystal, S. Honsawek, J. Litz, and E. Buchdunger
The Selective Tyrosine Kinase Inhibitor STI571 Inhibits Small Cell Lung Cancer Growth
Clin. Cancer Res.,
August 1, 2000;
6(8):
3319 - 3326.
[Abstract]
[Full Text]
|
|
|
|
|
|
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M. C. Heinrich, D. J. Griffith, B. J. Druker, C. L. Wait, K. A. Ott, and A. J. Zigler
Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor
Blood,
August 1, 2000;
96(3):
925 - 932.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
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F. X. Mahon, M. W. N. Deininger, B. Schultheis, J. Chabrol, J. Reiffers, J. M. Goldman, and J. V. Melo
Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance
Blood,
August 1, 2000;
96(3):
1070 - 1079.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
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E. Weisberg and J. D. Griffin
Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines
Blood,
June 1, 2000;
95(11):
3498 - 3505.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Horita, E. J. Andreu, A. Benito, C. Arbona, C. Sanz, I. Benet, F. Prosper, and J. L. Fernandez-Luna
Blockade of the Bcr-Abl Kinase Activity Induces Apoptosis of Chronic Myelogenous Leukemia Cells by Suppressing Signal Transducer and Activator of Transcription 5-Dependent Expression of Bcl-XL
J. Exp. Med.,
March 20, 2000;
191(6):
977 - 984.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Yano, R. S. Herbst, H. Shinohara, B. Knighton, C. D. Bucana, J. J. Killion, J. Wood, and I. J. Fidler
Treatment for Malignant Pleural Effusion of Human Lung Adenocarcinoma by Inhibition of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Phosphorylation
Clin. Cancer Res.,
March 1, 2000;
6(3):
957 - 965.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
H. Kantarjian, J. V. Melo, S. Tura, S. Giralt, and M. Talpaz
Chronic Myelogenous Leukemia: Disease Biology and Current and Future Therapeutic Strategies
Hematology,
January 1, 2000;
2000(1):
90 - 109.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. G. Wickremasinghe and A. V. Hoffbrand
Biochemical and Genetic Control of Apoptosis: Relevance to Normal Hematopoiesis and Hematological Malignancies
Blood,
June 1, 1999;
93(11):
3587 - 3600.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Wetzler, R. K. Dodge, K. Mrozek, A. J. Carroll, R. Tantravahi, A. W. Block, M. J. Pettenati, M. M. L. Beau, S. R. Frankel, C. C. Stewart, et al.
Prospective Karyotype Analysis in Adult Acute Lymphoblastic Leukemia: The Cancer and Leukemia Group B Experience
Blood,
June 1, 1999;
93(11):
3983 - 3993.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Wisniewski, A. Strife, S. Swendeman, H. Erdjument-Bromage, S. Geromanos, W. M. Kavanaugh, P. Tempst, and B. Clarkson
A Novel SH2-Containing Phosphatidylinositol 3,4,5-Trisphosphate 5-Phosphatase (SHIP2) Is Constitutively Tyrosine Phosphorylated and Associated With src Homologous and Collagen Gene (SHC) in Chronic Myelogenous Leukemia Progenitor Cells
Blood,
April 15, 1999;
93(8):
2707 - 2720.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. H. Tomasson, I. R. Williams, R. Hasserjian, C. Udomsakdi, S. M. McGrath, J. Schwaller, B. Druker, and D. G. Gilliland
TEL/PDGFbeta R Induces Hematologic Malignancies in Mice That Respond to a Specific Tyrosine Kinase Inhibitor
Blood,
March 1, 1999;
93(5):
1707 - 1714.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. R. LaMontagne Jr., G. Hannon, and N. K. Tonks
Protein tyrosine phosphatase PTP1B suppresses p210 bcr-abl-induced transformation of Rat-1 fibroblasts and promotes differentiation of K562 cells
PNAS,
November 24, 1998;
95(24):
14094 - 14099.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Shangary, K. D. Brown, A. W. Adamson, S. Edmonson, B. Ng, T. K. Pandita, J. Yalowich, G. E. Taccioli, and R. Baskaran
Regulation of DNA-dependent Protein Kinase Activity by Ionizing Radiation-activated Abl Kinase Is an ATM-dependent Process
J. Biol. Chem.,
September 22, 2000;
275(39):
30163 - 30168.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Sun, J. Zhao, M. A. Schwartz, J. Y. J. Wang, T. Wiedmer, and P. J. Sims
c-Abl Tyrosine Kinase Binds and Phosphorylates Phospholipid Scramblase 1
J. Biol. Chem.,
July 27, 2001;
276(31):
28984 - 28990.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
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Abstract
Introduction
Abstract
