Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells

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The bcr–abl oncogene, present in 95% of patients with chronic myelogenous leukemia (CML), has been implicated as the cause of this disease. A compound, designed to inhibit the Abl protein tyrosine kinase, was evaluated for its effects on cells containing the Bcr–Abl fusion protein. Cellular proliferation and tumor formation by Bcr–Abl–expressing cells were specifically inhibited by this compound. In colony–forming assays of peripheral blood or bone marrow from patients with CML, there was a 92–98% decrease in the number of bcr–abl colonies formed but no inhibition of normal colony formation. This compound may be useful in the treatment of bcr–abl–positive leukemias.

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  1. 1

    Kantarjian, H.M., Deisseroth, A.B., Kurzrock, R., Estrov, Z., & Talpaz, M., Chronic myelogenous leukemia: A concise update. Blood 82, 691–703 (1993).

  2. 2

    Allan, N.C., Shepard, P.C.A. & Richards, R.M. Interferon alpha prolongs survival for patients with CML in chronic phase: Preliminary results of the UK MRC randomized multicenter trial. Blood 84, 382a (1994).

  3. 3

    The Italian Cooperaticellve Study Group on Chronic Myeloid Leukemia. Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N. Engl. J. Med. 330, 820–825 (1994).

  4. 4

    Ozer, H., et al. Prolonged subcutaneous administration of recombinant alpha 2b interferon in patients with previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leukemia: Effect on remission duration and survival: Cancer and Leukemia Group B Study 8583. Blood. 82, 2975–2984 (1993).

  5. 5

    O'Brien, S.G. & Goldman, J.M. Autografting in chronic myeloid leukaemia. Blood Rev. 8, 63–69 (1994).

  6. 6

    McGlave, P.B., et al. Autologous transplants for chronic myelogenous leukaemia: Results from eight transplant groups. Lancet 343, 1486–1488 (1994).

  7. 7

    O'Brien, S.G. & Goldman, J.M. Current approaches to hematopoietic stem-Cell purging in chronic myeloid leukemia. J. Clin. Oncol. 13, 541–546 (1995).

  8. 8

    Nowell, P.C. & Hungerford, D.A. A minute chromosome in human chronic granulocytic leukemia. Science 132, 1497–1501 (1960).

  9. 9

    Rowley, J.D. A new consistent abnormality in chronic myelogenous leukaemia identified by quinacrine, fluorescence and Giemsa staining. Nature. 243, 290–293 (1973).

  10. 10

    Heisterkamp, N., et al. Localization of the c-abl oncogene adjacent to a translocation break point in chronic myelocytic leukemia. Nature. 306, 239–242 (1983).

  11. 11

    Bartram, C.R. et al. Translocation of c-abl correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukemia. Nature. 306, 277–280 (1983).

  12. 12

    Shtivelman, E., Lifshitz, B., Gale, R.P. & Canaani, E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature. 315, 550–554 (1985).

  13. 13

    Clark, S.S., et al. Expression of a distinctive BCR-ABL oncogene in Ph1-positive acute lymphocytic leukemia (ALL). Science. 239, 775–777 (1988).

  14. 14

    Scott, M.L., Van Etten, R., Daley, G.Q. & Baltimore, D. v-abl causes hematopoietic disease distinct from that caused by bcr-abl. Proc. Natl. Acad. Sci. USA. 88, 6506–6510 (1991).

  15. 15

    Kelliher, M.A., McLaughlin, J., Witte, O.N. & Rosenberg, N. Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL. Proc. Natl. Acad. Sci. USA. 87, 6649–6653 (1990).

  16. 16

    Daley, G.Q., Van Etten, R.A. & Baltimore, D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 247, 824–830 (1990).

  17. 17

    Oda, T., Tamura, S., Matsuguchi, T., Griffin, J.D. & Druker, B.J. The SH2 domain of Abl is not required for factor independent growth induced by Bcr-Abl in a murine myeloid Cell line. Leukemia. 9, 295–301 (1995).

  18. 18

    Lugo, T.G., Pendergast, A.M., Muller, A.J. & Witte, O.N. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science. 247, 1079–1082 (1990).

  19. 19

    Yaish, P., Gazit, A., Gilon, C. & Levitzki, A. Blocking of EGF-dependent cell proliferation by EGF receptor kinase inhibitors. Science 242, 933–935 (1988).

  20. 20

    Levitzki, A. & Gazit, A. Tyrosine kinase inhibition: An approach to drug development. Science. 267, 1782–1788 (1995).

  21. 21

    Kaur, G., et al. Tyrphostin induced growth inhibition: Correlation with effect on p210bcr-abl autokinase activity in K562 chronic myelogenous leukemia. Anti-Cancer Drugs. 5, 213–222 (1994).

  22. 22

    Anafi, M., Gazit, A., Zehavi, A., Ben-Neriah, Y. & Levitzki, A. Tyrphostin-induced inhibition of p210bcr-abl tyrosine kinase activity induces K562 to differentiate. Blood. 82, 3524–3529 (1993).

  23. 23

    Furet, P., et al. Modeling study of protein kinase inhibitors – binding mode of staurosporine and origin of the selectivity of CGP 52411. J Comput. Aided Mol. Des. 9, 465–472 (1995).

  24. 24

    Laneuville, P., Heisterkamp, N. & Groffen, J. Expression of the chronic myelogenous leukemia-associated p210bcr/abl oncoprotein in a murine IL-3 dependent myeloid Cell line. Oncogene 6, 275–282 (1991).

  25. 25

    Matulonis, U., Salgia, R., Okuda, K., Druker, B. & Griffin, J.D. IL-3 and p210BCR/ABL activate both unique and overlapping pathways of signal transduction in a factor-dependent myeloid Cell line. Exp. Hematol. 21, 1460–1466 (1993).

  26. 26

    Daley, G.Q. & Baltimore, D. Transformation of an interleukin 3-dependent hematopoietic Cell line by the chronic myelogenous leukemia-specific P210bcr/abl protein. Proc. Natl. Acad. Sci. USA. 85, 9312–9316 (1988).

  27. 27

    Honma, Y., Okabe, K.J., Hozumi, M., Uehara, Y. & Mizuno, S. Induction of ery-throid differentiation of K562 human leukemic cells by herbimycin A, an inhibitor of tyrosine kinase activity. Cancer Res. 49, 331–4 (1989).

  28. 28

    Schwartzberg, P.L., et al. Mice homozygous for the ablm1 mutation show poor viability and depletion of selected B and T Cell populations. Cell. 65, 1165–1175 (1991).

  29. 29

    Sawyers, C.L., McLaughlin, J., Goga, A., Havlik, M. & Witte, O. The nuclear tyrosine kinase c-Abl negatively regulates Cell growth. Cell. 77, 121–131 (1994).

  30. 30

    Silvennoinen, O., et al. Structure of the murine Jak2 protein-tyrosine kinase and its role in interleukin 3 signal transduction. Proc. Natl. Acad. Sci. USA. 90, 8429–8433 (1993).

  31. 31

    Caracciolo, D., et al. Lineage-specific requirement of c-abl function in normal hematopoiesis. Science. 245, 1107–1110 (1989).

  32. 32

    Martiat, P., et al. Retrovirally transduced antisense sequences stably suppress p210BCR-ABL expression and inhibit the proliferation of BCR/ABL-containing Cell lines. Blood. 81, 502–509 (1993).

  33. 33

    Oda, T., et al. CRKL is the major tyrosine phosphorylated protein in neutrophils from patients with chronic myelogenous leukemia. J. Biol. Chem. 269, 22925–22928 (1994).

  34. 34

    Evans, C.A., Owen-Lynch, P.J., Whetton, A.D. & Dive, C. Activation of the Abelson tyrosine kinase activity is associated with suppression of apoptosis in hemopoietic Cells. Cancer Res. 53, 1735–1738 (1993).

  35. 35

    Bedi, A., Zehnbauer, B.A., Barber, J.P., Sharkis, S.J. & Jones, R.J. Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia. Blood. 83, 2038–2044 (1994).

  36. 36

    Heldin, C.H. & Westermark, B. Platelet-derived growth factor: Mechanism of action and possible in vivo function. Cell Regul. 1, 555–566 (1990).

  37. 37

    Kanakura, Y., et al. Signal transduction of the human granulocyte-macrophage colony-stimulating factor and interleukin-3 receptors involves a common set of cytoplasmic proteins. Blood. 76, 706–715 (1990).

  38. 38

    Greenberger, J.S., Sakakeeny, M.A., Humphries, R.K., Eaves, C.J., & Eckner, R.J. Demonstration of permanent factor-dependent multipotential (erythroid/neu-trophil/basophil) hematopoietic progenitor cell lines. Proc. Natl. Acad. Sci. USA. 80, 2391–2395 (1983).

  39. 39

    Avanzi, G.C., et al. Selective growth response to IL-3 of a human leukaemic Cell line with megakaryoblastic features. Br. J. Haematol. 69, 359–366 (1988).

  40. 40

    Matsuguchi, T., et al. 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, 5016–5021 (1994).

  41. 41

    Erwin, J.L. & Anderson, S.M. Analysis of phosphotyrosine-containing proteins present in v-src-infected myeloid progenitor cells. Oncogene 7, 1101–1107 (1992).

  42. 42

    Mossman, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods 65, 55–63 (1983).

  43. 43

    Orkin, S.H., Harosi, F.I. & Leder, P. Differentiation in erythroleukemia cells and their somatic hybrids. Proc. Natl. Acad. Sci. USA. 72, 98–102 (1975).

  44. 44

    Buchdunger, E., et al. 4,5-Dianilinophthalimide: A protein-tyrosine kinase inhibitor with selectivity for the epidermal growth factor receptor signal transduction pathway and potent in vivo antitumor activity. Proc. Natl. Acad. Sci. USA. 91, 2334–2338 (1994).

  45. 45

    Buchdunger, E., et al. Selective inhibition of the platelet-derived growth factor signal transduction pathway by a protein-tyrosine kinase inhibitor of the 2-phenylaminopyrimidine class. Proc. Natl. Acad. Sci. USA 92, 2558–2562 (1995).

  46. 46

    Arion, D., Meijer, L., Brizuela, L. & Beach, D. cdc2 is a component of the M phase-specific histone HI kinase: Evidence for identity with MPF. Cell. 55, 371–378 (1988).

  47. 47

    Pendergast, A.M., et al. Evidence for regulation of the human ABL tyrosine kinase by a cellular inhibitor. Proc. Natl. Acad. Sci. USA. 88, 5927–5931 (1991).

  48. 48

    Kharbanda, S., et al. Activation of the c-abl tyrosine kinase in stress response to DNA-damaging agents. Nature. 376, 785–788 (1995).

  49. 49

    Evans, B.D., Smith, I.E., Shorthouse, A.J. & Millar, J.L. A comparison of the response of human lung carcinoma xenografts to vindesine and vincristine. Br. J. Cancer. 45, 466–468 (1982).

  50. 50

    Segal, G.M., et al. Repression of Fanconi anemia gene (FACC) expression inhibits growth of hematopoietic progenitor Cells. J. Clin. Invest. 94, 846–852 (1994).

  51. 51

    Hernandez, A., et al. Detection of the hybrid BCR/ABL messenger RNA in single CFU-GM colonies using the polymerase chain reaction. Exp. Hematol. 18, 1142–1144 (1990).

  52. 52

    Dunn, O.J. Multiple comparisons using rank sums. Technometrics 6, 241–252 (1964).

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