Transformation of Myeloid Cells by the BCR/ABL Oncogene

  • J. D. Griffin
  • M. Sattler
  • N. Uemura
  • K. Okuda
  • R. Salgia
Conference paper
Part of the Haematology and Blood Transfusion / Hämatologie und Bluttransfusion book series (HAEMATOLOGY, volume 39)

Abstract

BCR/ABL transforms hematopoietic cells in vitro and in vivo and exerts a wide variety of biological effects, including induction of factor-independence, reduction of apoptosis, and altering adhesion of CML cells to marrow stroma. However, at a biochemical level, the mechanisms by which BCR/ABL transforms myeloid cells remain poorly understood. p210BCR/ABL has elevated ABL tyrosine kinase activity, relocates to the cytoskeleton, and phosphorylates many cellular signaling proteins. Recent advances in identifying the substrates of the ABL tyrosine kinase have led to a better understanding of the mechanism of transformation. A variety of signaling pathways are activated by p210BCR/ABL, including those involving p2lras, PI3K, and CRKL. Considerable progress has been made linking each of these pathways to specific biological and clinical abnormalities in CML.

Keywords

Tyrosine Leukemia Proline Oligomerization Interferon 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Nowell PC, Hungerford DA (1960) A minute chromosome in human chronic granulocytic leukemia. J Natl Cancer Inst 25: 85–109PubMedGoogle Scholar
  2. 2.
    Kurzrock R, Gutterman JU, Talpaz M (1988) The molecular genetics of Philadelphia chromosome-positive leukemias. New Engl J Med 319: 990–998PubMedCrossRefGoogle Scholar
  3. 3.
    Witte ON (1993) Role of the BCR-ABL oncogene in human leukemia: fifteenth Richard and Hin-da Rosenthal Foundation Award Lecture. [Review] Cancer Research 53: 485–489PubMedGoogle Scholar
  4. 4.
    Voncken JW, van Schaick H, Kaartinen V, Deemer K, Coates T, Landing B, Pattengale P, Dorseuil O, Bokoch GM, Groffen J, et al. (1995) Increased neutrophil respiratory burst in bcr-null mutants. Cell 80: 719–728PubMedCrossRefGoogle Scholar
  5. 5.
    Chuang TH, Xu X, Kaartinen V, Heisterkamp N, Groffen J, Bokoch GM (1995) Abr and Bcr are multifunctional regulators of the Rho GTPbinding protein family. Proceedings of the National Academy of Sciences of the United States of America 92: 10282–10286PubMedCrossRefGoogle Scholar
  6. 6.
    Lugo TG, Pendergast AM, Muller AJ, Witte ON (1990) Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 247: 1079–1082PubMedCrossRefGoogle Scholar
  7. 7.
    Pane F, Frigeri F, Sindona M, Luciano L, Ferrara F, Cimino R, Meloni G, Saglio G, Salvatore F, Rotoli B (1996) Neutrophilic-chronic myeloid leukemia: a distinct disease with a specific molecular marker (BCR/ABL with C3/A2 junction) [see comments]. Blood 88: 2410–2414PubMedGoogle Scholar
  8. 8.
    Daley GQ, McLaughlin J, Witte ON, Baltimore D (1987) The CML-specific p210bcr/abl protein, unlike v-abl, does not transform NIH/3T3 fibroblasts. Science 237: 532–538PubMedCrossRefGoogle Scholar
  9. 9.
    Pendergast AM, Gishizky ML, Havlik MH, Witte ON (1993) SH1 domain autophosphorylation of P210 BCR/ABL is required for transformation but not growth factor independence. Molecular & Cellular Biology 13: 1728–1736Google Scholar
  10. 10.
    McWhirter JR, Galasso DL, Wang JY (1993) A coiled-coil oligomerization domain of Bcr is essential for the transforming function of Bcr-Abl oncoproteins. Molecular & Cellular Biology 13: 7587–7595Google Scholar
  11. 11.
    Okuda K, Van Etten R, D’Andrea AD, Griffin JD (1996) Construction of a ligand-regulated ABL tyrosine kinase which mimics the biological effects of BCR/ABL in hematopoietic cells. Blood 88: 674aGoogle Scholar
  12. 12.
    Wetzler M, Talpaz M, Van Etten RA, Hirsh-Ginsberg C, Beran M, Kurzrock R (1993) Subcellular localization of Bcr, Abl, and Bcr-Abl proteins in normal and leukemic cells and correlation of expression with myeloid differentiation. Journal of Clinical Investigation 92: 1925–1939PubMedCrossRefGoogle Scholar
  13. 13.
    Van Etten RA, Jackson PK, Baltimore D, Sanders MC, Matsudaira PT, Janmey PA (1994) The COOH terminus of the c-Abl tyrosine kinase contains distinct F- and G-actin binding domains with bundling activity [published erratum appears in J Cell Biol 1994 Mar;124(5):865]. Journal of Cell Biology 124: 325–340PubMedCrossRefGoogle Scholar
  14. 14.
    MacKenzie E, Stewart E, Birnie GD (1993) ABLBCR mRNAs transcribed from chromosome 9q+ in Philadelphia-chromosome-positive chronic myeloid leukaemia. Leukemia 7: 702706Google Scholar
  15. 15.
    McWhirter JR, Wang JY (1993) An actin-binding function contributes to transformation by the Bcr-Abl oncoprotein of Philadelphia chromosome-positive human leukemias. Embo Journal 12: 1533–1546PubMedGoogle Scholar
  16. 16.
    Salgia R, Sattler M, Pisick E, Li JL, Griffin JD (1996) P210(bcr/abl) induces formation of complexes containing focal adhesion proteins and the protooncogene product p120(c-cbl). Experimental Hematology 24: 310–313PubMedGoogle Scholar
  17. 17.
    Salgia R, Brunkhorst B, Pisick E, Li J-L, Lo SH, Chen LB, Griffin JD (1995) Increased tyrosine phosphorylation of focal adhesion proteins in myeloid cell lines expressing p210BCR/ABL. Oncogene 11: 1149–1155PubMedGoogle Scholar
  18. 18.
    Muller AJ, Young JC, Pendergast AM, Pondel M, Landau NR, Littman DR, Witte ON (1991) BCR first exon sequences specifically activate the BCR/ABL tyrosine kinase oncogene of Philadelphia chromosome-positive human leukemias. Molecular & Cellular Biology 11: 1785–1792Google Scholar
  19. 19.
    Gertler F, Niebuher K, Reinhard M, Wehland J, Soriano P (1996) Mena, a relative of VASP and drosophilia enabled, is implicated in the control of microfilament dynamics. Cell 87: 227–239PubMedCrossRefGoogle Scholar
  20. 20.
    Cicchetti P, Mayer BJ, Thiel G, Baltimore D (1992) Identification of a protein that binds to the SH3 region of Abl and is similar to Bcr and GAP-rho. Science 257: 803–806PubMedCrossRefGoogle Scholar
  21. 21.
    Pendergast AM, Quilliam LA, Cripe LD, Bassing CH, Dai Z, Li N, Batzer A, Rabun KM, Der CJ, Schlessinger J, et a (1993) BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Cell 75: 175–185PubMedGoogle Scholar
  22. 22.
    Puil L, Liu J, Gish G, Mbamalu G, Bowtell D, Pe-licci TG, Arlinghaus R, Pawson T (1994) Bcr-Abl oncoproteins bind directly to activators of the ras signalling pathway. EMBO Journal 13: 764–773PubMedGoogle Scholar
  23. 23.
    Afar DEA, Goga A, McLaughlin J, Witte ON, Sawyers C (1994) Differential complementation of Bcr-Abl point mutants with c-Myc. Science 264: 424–426PubMedCrossRefGoogle Scholar
  24. 24.
    Senechal K, Halpern J, Sawyers CL (1996) The CRKL adaptor protein transforms fibroblasts and functions in transformation by the BCRABL oncogene. Journal of Biological Chemistry 271: 23255–23261PubMedCrossRefGoogle Scholar
  25. 25.
    Kipreos ET, Wang JY (1990) Differential phosphorylation of c-Abl in cell cycle determined by cdc2 kinase and phosphatase activity. Science 248: 217–220PubMedCrossRefGoogle Scholar
  26. 26.
    Kipreos ET, Wang JY (1992) Cell cycle-regulated binding of c-Abl tyrosine kinase to DNA. Science 256: 382–385PubMedCrossRefGoogle Scholar
  27. 27.
    Welch PJ, Wang JY (1993) A C-terminal protein-binding domain in the retinoblastoma protein regulates nuclear c-Abl tyrosine kinase in the cell cycle. Cell 75: 779–790PubMedCrossRefGoogle Scholar
  28. 28.
    Kharbanda S, Ren R, Pandey P, Shafman TD, Feller SM, Weichselbaum RR, Kufe DW (1995) Activation of the c-Abl tyrosine kinase in the stress response to DNA-damaging agents. Nature 376: 785–788PubMedCrossRefGoogle Scholar
  29. 29.
    Metcalf D, Moore MA, Sheridan JW, Spitzer G (1974) Responsiveness of human granulocytic leukemic cells to colony-stimulating factor. Blood 43: 847–859PubMedGoogle Scholar
  30. 30.
    Metcalf D, Moore MA (1975) Growth and responsiveness of human granulocytic leukemic cells in vitro. Bibliotheca Haematologica 40: 235241Google Scholar
  31. 31.
    Daley G, Baltimore D (1988) Transformation of an interleukin-3-dependent hematopoietic cell line by the chronic myelogenous leukemia-specific p210 BCR/ABL protein. Proc Nati Acad Sci USA 85: 9312CrossRefGoogle Scholar
  32. 32.
    Bedi A, Zehnbauer BA, Barber JP, Sharkis SJ, Jones RJ (1994) Inhibition of apoptosis by BCRABL in chronic myeloid leukemia. Blood 83: 2038–2044PubMedGoogle Scholar
  33. 33.
    Evans CA, Owen-Lynch PJ, Whetton AD, Dive C (1993) Activation of the Abelson tyrosine kinase activity is associated with suppression of apoptosis in hemopoietic cells. Cancer Research 53: 1735–1738PubMedGoogle Scholar
  34. 34.
    Laneuville P, Timm M, Hudson AT (1994) bcr/abl expression in 32D c13(G) cells inhibits apoptosis induced by protein tyrosine kinase inhibitors. Cancer Research 54: 1360–1366PubMedGoogle Scholar
  35. 35.
    Smetsers TF, Skorski T, van de Locht LT, Wessels HM, Pennings AH, de Witte T, Calabretta B, Mensink EJ (1994) Antisense BCR-ABL oligonucleotides induce apoptosis in the Philadelphia chromosome-positive cell line BV 173. Leukemia 8: 129–140PubMedGoogle Scholar
  36. 36.
    Carlesso N, Griffin JD, Druker BJ (1994) Use of a temperature sensitive mutant to define the biological effects of the p210bcr/abl tyrosine kinase on proliferation of a factor-dependent murine myeloid cell line. Oncogene 9: 149–156PubMedGoogle Scholar
  37. 37.
    Verfaillie CM, McCarthy JB, McGlave PB (1992) Mechanisms underlying abnormal trafficking of malignant progenitors in chronic myelogenous leukemia. Journal of Clinical Investigation 90: 1232–1241PubMedCrossRefGoogle Scholar
  38. 38.
    Bhatia R,Wayner EA, McGlave PB, Verfaillie CM (1994) Interferon-alpha restores normal adhesion of chronic myelogenous leukemia hematopoietic progenitors to bone marrow stroma by correcting impaired beta 1 integrin receptor function [see comments]. Journal of Clinical Investigation 94: 384–391PubMedCrossRefGoogle Scholar
  39. 39.
    Hynes RO (1992) Integrin: versatility, modulation, and signaling in cell adhesion. Cell 69: 1125CrossRefGoogle Scholar
  40. 40.
    Larson R, Springer T (1990) Structure and function of leukocyte integrins. Immunological Reviews 114: 181–217PubMedCrossRefGoogle Scholar
  41. 41.
    Romer L,Burridge K, Turner C (1993) Signalling between the extracellular matrix and the cytoskeleton: tyrosine phosphorylation and focal adhesion assembly. Cold Spring Harbor Symp Quant Biol 62: 193–201Google Scholar
  42. 42.
    Burridge K, Turner CE, Romer LH (1992) Tyrosine phosphorylation of paxillin and pp125FAK accompanies cell adhesion to extracellular matrix: a role in cytoskeletal assembly. Journal of Cell Biology 119: 893–903PubMedCrossRefGoogle Scholar
  43. 43.
    Guan J-L, Shaloway D (1992) Regulation of focal adhesion-associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation. Nature 358: 690–692PubMedCrossRefGoogle Scholar
  44. 44.
    Kornberg L, Earp H, Parsons J, Schaller M, Juliano R (1992) Cell adhesion or integrin clustering increases phosphorylation of a focal adhesion-associated tyrosine kinase. J Biol Chem 267: 23439–23442PubMedGoogle Scholar
  45. 45.
    Burridge K, Fath K, Kelly T, Nuckolls G, Turner C: Focal adhesions (1988) Transmembrane junctions between the extracellular matrix and the cytoskeleton. Ann Rev Cell Biol 4: 487–525PubMedCrossRefGoogle Scholar
  46. 46.
    Lo S, Chen L (1994) Focal adhesion as a signal tranduction organelle. Cancer and Metastasis Reviews 13: 9–24PubMedCrossRefGoogle Scholar
  47. 47.
    Schaller M, Borgman C, Cobb B, Vines R, Reynolds A, Parsons J (1992) pp125FAK, a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc Natl Acad Sci USA 89: 5192–5196Google Scholar
  48. 48.
    Hanks S, Calalb M, Harper M, Patel S (1992) Focal adhesion-protein kinase phosphorylated in response to cell attachment to fibronectin. Proc Natl Acad Sci USA 89: 8487–8491PubMedCrossRefGoogle Scholar
  49. 49.
    Mayer BJ, Hanafusa H (1990) Association of the v-crk oncogene product with phosphotyrosinecontaining proteins and protein kinase activity. Proceedings of the National Academy of Sciences of the United States of America 87: 2638–2642PubMedCrossRefGoogle Scholar
  50. 50.
    Fukai Y, O’Brien MC, Hanafusa H (1991) Deletions in the SH2 domain of p60v-src prevent association with the detergent-insoluble cellular matrix. Mol Cell Biol 11: 1207–1213Google Scholar
  51. 51.
    Zachary I, Rozengurt E (1992) Focal adhesion kinase (p125F“K): a point of convergence in the action of neuropeptides, integrins, and oncogenes. Cell 71: 891–894PubMedCrossRefGoogle Scholar
  52. 51.
    Zachary I, Rozengurt E (1992) Focal adhesion kinase (p125F“K): a point of convergence in the action of neuropeptides, integrins, and oncogenes. Cell 71: 891–894PubMedCrossRefGoogle Scholar
  53. 53.
    Weng Z, Taylor J, Turner C, Brugge J, Seidel-Dugan C (1993) Detection of src-SH3 binding proteins, including paxillin, in normal and v-srctransformed BALB/c3T3 cells. J Biol Chem 268: 14956–14963PubMedGoogle Scholar
  54. 54.
    Birge RB, Fajardo JE, Reichman C, Shoelson SE, Songyang Z, Cantley LC, Hanafusa H (1993) Identification and characterization of a high-af-finity interaction between v-Crk and tyrosinephosphorylated paxillin in CT10-transformed fibroblasts. Molecular & Cellular Biology 13: 4648–4656Google Scholar
  55. 55.
    ten Hoeve J, Arlinghaus RB, Guo JQ, Heisterkamp N, Groffen J (1994) Tyrosine phosphorylation of CRKL in Philadelphia+ leukemia. Blood 84: 1731–1736PubMedGoogle Scholar
  56. 56.
    ten Hoeve J, Kaartinen V, Fioretos T, Haataja L, Voncken JW, Heisterkamp N, Groffen J (1994) Cellular interactions of CRKL, and SH2–SH3 adaptor protein. Cancer Research 54: 2563–2567PubMedGoogle Scholar
  57. 57.
    Oda T, Heaney C, Hagopian JR, Okuda K, Griffin JD, Druker BJ (1994) Crkl is the major tyrosinephosphorylated protein in neutrophils from patients with chronic myelogenous leukemia. Journal of Biological Chemistry 269: 22925–22928PubMedGoogle Scholar
  58. 58.
    Matsuda M, Mayer BJ, Hanafusa H (1991) Identification of domains of the v-crk oncogene product sufficient for association with phosphotyrosine-containing proteins. Molecular & Cellular Biology 11: 1607–1613Google Scholar
  59. 59.
    ten Hoeve J, Morris C, Heisterkamp N, Groffen J (1993) Isolation and chromosomal localization of CRKL, a human crk-like gene. Oncogene 8: 2469–2474PubMedGoogle Scholar
  60. 60.
    Sattler M, Salgia R, Okuda K, Uemura N, Durstin MA, Pisick E, Xu G, Li JL, Prasad KV, Griffin JD (1996) The proto-oncogene product p120CBL and the adaptor proteins CRKL and c-CRK link c-ABL, p190BCR/ABL and p210BCR/ABL to the phosphatidylinositol-3’ kinase pathway. Oncogene 12: 839–846PubMedGoogle Scholar
  61. 61.
    Sattler M, Salgia R, Griffin JD (1996) Crkl binds c-Cbl in response to integrin activation. (submitted)Google Scholar
  62. 62.
    Salgia R, Sattler M, Pisick E, Li JL, Griffin JD (1996) p210BCR/ABL induces formation of complexes containing focal adhesion proteins and the protooncogene product p120c-Cbl. Experimental Hematology 24: 310–313PubMedGoogle Scholar
  63. 63.
    Salgia R, Pisick E, Sattler M, Li JL, Uemura N, Wong WK, Burky SA, Hirai H, Chen LB, Griffin JD (1996) p130CAS forms a signaling complex with the adapter protein CRKL in hematopoietic cells transformed by the BCR/ABL oncogene. Journal of Biological Chemistry 271:25198–25203PubMedCrossRefGoogle Scholar
  64. 64.
    Salgia R, Uemura N, Okuda K, Li JL, Pisick E, Sattler M, de Jong R, Druker B, Heisterkamp N, Chen LB, Griffin JD (1995) CRKL links p210BCR/ABL with paxillin in chronic myelogenous leukemia cells. Journal of Biological Chemistry 270: 29145–29150PubMedCrossRefGoogle Scholar
  65. 65.
    Salgia R, Li J-L, Curry E, Pisick E, Ewaniuk D, Burky SA, Ernst T, Sattler M, Chen LB, Griffin JD (1996) Transformation of hematopoietic cells by BCR/ABL is associated with enhanced motility. Blood 88: 674aGoogle Scholar
  66. 66.
    Holtschke T, Lohler J, Kanno Y, Fehr T, Giese N, Rosenbauer F, Lou J, Knobeloch KP, Gabriele L, Waring JF, Bachmann MF, Zinkernagel RM, Morse Hr, Ozato K, Horak I (1996) Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Cell 87: 307–317PubMedCrossRefGoogle Scholar
  67. 67.
    Sawyers CL, Callahan W, Witte ON (1992) Dominant negative MYC blocks transformation by ABL oncogenes. Cell 70: 901–910PubMedCrossRefGoogle Scholar
  68. 68.
    Afar DE, McLaughlin J, Sherr CJ, Witte ON, Roussel MF (1995) Signaling by ABL oncogenes through cyclin Dl. Proceedings of the National Academy of Sciences of the United States of America 92: 9540–9544PubMedCrossRefGoogle Scholar
  69. 69.
    Tauchi T, Boswell HS, Leibowitz D, Broxmeyer HE (1994) Coupling between p210bcr-abl and Shc and Grb2 adaptor proteins in hematopoietic cells permits growth factor receptor-independent link to ras activation pathway. Journal of Experimental Medicine 179: 167–175PubMedCrossRefGoogle Scholar
  70. 70.
    Druker B, Okuda K, Matulonis U, Salgia R, Roberts T, Griffin JD (1992) Tyrosine phosphorylation of rasGAP and associated preteins in chronic myelogenous leukemia cell lines. Blood 79: 2215–2220PubMedGoogle Scholar
  71. 71.
    Mandanas RA, Leibowitz DS, Gharehbaghi K, Tauchi T, Burgess GS, Miyazawa K, Jayaram HN, Boswell HS (1993) Role of p21 RAS in p210 bcrabl transformation of murine myeloid cells. Blood 82: 1838–1847PubMedGoogle Scholar
  72. 72.
    Skorski T, Kanakaraj P, Ku DH, NieborowskaSkorska M, Canaani E, Zon G, Perussia B, Calabretta B (1994) Negative regulation of p120GAP GTPase promoting activity by p210bcr/abl: implication for RAS-dependent Philadelphia chromosome positive cell growth. Journal of Experimental Medicine 179: 1855–1865PubMedCrossRefGoogle Scholar
  73. 73.
    de Jong R, ten Hoeve J, Heisterkamp N, Groffen J (1995) Crkl is complexed with tyrosine-phosphorylated Cbl in Ph-positive leukemia. Journal of Biological Chemistry 270: 21468–21471PubMedCrossRefGoogle Scholar
  74. 74.
    Okuda K, Golub TR, Gilliland DG, Griffin JD (1996) p210BCR/ABL, p190BCR/ABL, and TEL/ABL activate similar signal transduction pathways in hematopoietic cell lines. Oncogene 13: 1147–1152PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • J. D. Griffin
    • 1
  • M. Sattler
    • 1
  • N. Uemura
    • 1
  • K. Okuda
    • 1
  • R. Salgia
    • 1
  1. 1.Dana-Farber Cancer InstituteBostonUSA

Personalised recommendations