Skip to main content
SpringerLink
Log in

Roles for Signaling Molecules in the Growth and Survival of CML Cells

  • Chapter
Molecular Pathogenesis and Treatment of Chronic Myelogenous Leukemia

  • 736 Accesses

Abstract

Chronic myelogenous leukemia (CML) is caused by the reciprocal chromosomal translocation t(9:22)(q34;q11). This translocation yields BCR-ABL fusion gene on derivative chromosome 22 called as Philadelphia (Ph) chromosome. Although several forms of BCR-ABL are generated according to the breakpoints in the BCR gene, p210 BCR-ABL is observed in more than 95 % of CML patients. In contrast to the nuclear localization of c-ABL, BCR-ABL is localized in the cytoplasm and acts as a constitutively active tyrosine kinase as a tetramer. BCR-ABL has several functional domains, through which it interacts with downstream signaling molecules and transmits leukemogenic signals: a coiled-coil motif, SH2 domain, Y177, and Dbl homology domain from BCR and SH3, SH2, SH1(kinase), CRKL-binding, and actin-binding domains from c-ABL. Through these domains, BCR-ABL activates Ras/MAPK, PI3K/Akt, and STATs, each of which contributes to excessive cell growth, survival, and consequent leukemic transformation. In addition, SHP-2, c-Cbl, Gab2, and CRKL are involved in the leukemogenic activities of BCR-ABL. Although tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis of CML patients in chronic phase, a small proportion of patients show resistance to TKIs due to point mutations of the BCR-ABL gene and/or BCR-ABL-independent activation of Src family tyrosine kinases such as Lyn and HCK. In addition, CML stem cells are known to resistant to TKIs, in which JAK2, Wnt/β-catenin, and Sonic hedgehog pathways are activated in a BCR-ABL independent manner and contribute to TKI resistance.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. McWhirter JR, et al. Activation of tyrosine kinase and microfilament-binding functions of c-abl by bcr sequences in bcr/abl fusion proteins. Mol Cell Biol. 1991;11(3):1553–65.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. McWhirter JR, et al. An actin-binding function contributes to transformation by the Bcr-Abl oncoprotein of Philadelphia chromosome-positive human leukemias. EMBO J. 1993;12(4):1533–46.

    PubMed Central  CAS  PubMed  Google Scholar 

  3. McWhirter JR, et al. A coiled-coil oligomerization domain of Bcr is essential for the transforming function of Bcr-Abl oncoproteins. Mol Cell Biol. 1993;13(12):7587–95.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Tauchi T, et al. A coiled-coil tetramerization domain of BCR-ABL is essential for the interactions of SH2-containing signal transduction molecules. J Biol Chem. 1997;272(2):1389–94.

    Article  CAS  PubMed  Google Scholar 

  5. Cortez D, et al. Structural and signaling requirements for BCR-ABL-mediated transformation and inhibition of apoptosis. Mol Cell Biol. 1995;15(10):5531–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Goga A, et al. Alternative signals to RAS for hematopoietic transformation by the BCR-ABL oncogene. Cell. 1995;82(6):981–8.

    Article  CAS  PubMed  Google Scholar 

  7. Maru Y, et al. The BCR gene encodes a novel serine/threonine kinase activity within a single exon. Cell. 1991;67(3):459–68.

    Article  CAS  PubMed  Google Scholar 

  8. Chuang TH, et al. Abl and Bcr are multifunctional regulators of the Rho GTP-binding protein family. Proc Natl Acad Sci U S A. 1995;92(22):10282–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Ramakrishnan L, et al. Abl genes. Biochim Biophys Acta. 1989;989(2):209–24.

    CAS  PubMed  Google Scholar 

  10. Ren R, et al. Identification of a ten-amino acid proline-rich SH3 binding site. Science. 1993;259(5098):1157–61.

    Article  CAS  PubMed  Google Scholar 

  11. Franz WM, et al. Deletion of an Nterminal regulatory domain of the c-abl tyrosine kinase activates its oncogenic potential. EMBO J. 1989;8(1):137–47.

    PubMed Central  CAS  PubMed  Google Scholar 

  12. Jackson P, et al. N-terminal mutations activate the leukemogenic potential of the myristoylated form of c-abl. EMBO J. 1989;8(2):449–56.

    PubMed Central  CAS  PubMed  Google Scholar 

  13. Jackson PK, et al. Mutation of a phenylalanine conserved in SH3-containing tyrosine kinases activates the transforming ability of c-Abl. Oncogene. 1993;8(7):1943–56.

    CAS  PubMed  Google Scholar 

  14. Mayer BJ, et al. Mutagenic analysis of the roles of SH2 and SH3 domains in regulation of the Abl tyrosine kinase. Mol Cell Biol. 1994;14(5):2883–94.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Maru Y, et al. Deletion of the ABL SH3 domain reactivates de-oligomerized BCR-ABL for growth factor independence. FEBS Lett. 1996;379(3):244–6.

    Article  CAS  PubMed  Google Scholar 

  16. Pendergast AM, et al. Evidence for regulation of the human ABL tyrosine kinase by a cellular inhibitor. Proc Natl Acad Sci U S A. 1991;88(13):5927–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Walkenhorst J, et al. Analysis of human c-Abl tyrosine kinase activity and regulation in S. pombe. Oncogene. 1996;12(7):1513–20.

    CAS  PubMed  Google Scholar 

  18. Wen ST, et al. The PAG gene product, a stress-induced protein with antioxidant properties, is an Abl SH3-binding protein and a physiological inhibitor of c-Abl tyrosine kinase activity. Genes Dev. 1997;11(19):2456–67.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Cicchetti P, et al. Identification of a protein that binds to the SH3 region of Abl and is similar to Bcr and GAP-rho. Science. 1992;257(5071):803–6.

    Article  CAS  PubMed  Google Scholar 

  20. Dai Z, et al. Abi-2, a novel SH3-containing protein interacts with the c-Abl tyrosine kinase and modulates c-Abl transforming activity. Genes Dev. 1995;9(21):2569–82.

    Article  CAS  PubMed  Google Scholar 

  21. Zhu J, et al. c-ABL tyrosine kinase activity is regulated by association with a novel SH3-domain-binding protein. Mol Cell Biol. 1996;16(12):7054–62.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Skorski T, et al. The SH3 domain contributes to BCR/ABL-dependent leukemogenesis in vivo: role in adhesion, invasion, and homing. Blood. 1998;91(2):406–18.

    CAS  PubMed  Google Scholar 

  23. Songyang Z, et al. SH2 domains recognize specific phosphopeptide sequences. Cell. 1993;72(5):767–78.

    Article  CAS  PubMed  Google Scholar 

  24. Skorski T, et al. Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. EMBO J. 1997;16(20):6151–61.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Afar DE, et al. Differential complementation of Bcr-Abl point mutants with c-Myc. Science. 1994;264(5157):424–6.

    Article  CAS  PubMed  Google Scholar 

  26. Mayer BJ, et al. Point mutations in the abl SH2 domain coordinately impair phosphotyrosine binding in vitro and transforming activity in vivo. Mol Cell Biol. 1992;12(2):609–18.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Ilaria RL, et al. The SH2 domain of p210bcr/abl is not required for the transformation of hematopoetic factor-dependent cells. Blood. 1995;86(10):3897–904.

    PubMed  Google Scholar 

  28. Barila D, et al. An intramolecular SH3-domain interaction regulates c-Abl activity. Nat Genet. 1998;18(3):280–2.

    Article  CAS  PubMed  Google Scholar 

  29. Moarefi I, et al. Activation of the Src-family tyrosine kinase Hck by SH3 domain displacement. Nature. 1997;385(6617):650–3.

    Article  CAS  PubMed  Google Scholar 

  30. Sicheri F, et al. Crystal structure of the Src family tyrosine kinase Hck. Nature. 1997;385(6617):602–9.

    Article  CAS  PubMed  Google Scholar 

  31. Grebien F, et al. Targeting the SH2-kinase interface in Bcr-Abl inhibits leukemogenesis. Cell. 2011;147(2):306–19.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Rowley PT, et al. The effect of bcr-abl antisense oligonucleotide on DNA synthesis and apoptosis in K562 chronic myeloid leukemia cells. Leuk Res. 1996;20(6):473–80.

    Article  CAS  PubMed  Google Scholar 

  33. Druker BJ, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2(5):561–6.

    Article  CAS  PubMed  Google Scholar 

  34. Deininger MW, et al. The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood. 1997;90(9):3691–8.

    CAS  PubMed  Google Scholar 

  35. Carroll M, et al. CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL and TEL-PDGFR fusion proteins. Blood. 1997;90(12):4947–52.

    CAS  PubMed  Google Scholar 

  36. O'Brien SG, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348(11):994–1004.

    Article  PubMed  Google Scholar 

  37. Kantarjian H, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346(24):645–52.

    Article  CAS  PubMed  Google Scholar 

  38. Druker BJ, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408–17.

    Article  CAS  PubMed  Google Scholar 

  39. Druker BJ, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344(14):1038–42.

    Article  CAS  PubMed  Google Scholar 

  40. le Coutre P, et al. Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood. 2000;95(5):1758–66.

    PubMed  Google Scholar 

  41. Mahon FX, et al. Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood. 2000;96(3):1070–9.

    CAS  PubMed  Google Scholar 

  42. Gorre ME, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293(5531):876–80.

    Article  CAS  PubMed  Google Scholar 

  43. Hochhaus A, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002;16(11):2190–6.

    Article  CAS  PubMed  Google Scholar 

  44. Apperley JF. Part II: management of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol. 2007;8(12):1116–28.

    Article  CAS  PubMed  Google Scholar 

  45. Branford S, et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood. 2003;102(1):276–83.

    Article  CAS  PubMed  Google Scholar 

  46. Quintás-Cardama A, et al. Molecular biology of bcr-abl1–positive chronic myeloid leukemia. Blood. 2009;113(8):1619–30.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  47. Cortes JE, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367(22):2075–88.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Cortes JE, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369(19):1783–96.

    Article  CAS  PubMed  Google Scholar 

  49. Zhang J, et al. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature. 2010;463(7280):501–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Heaney C, et al. Direct binding of CRKL to BCR-ABL is not required for BCR-ABL transformation. Blood. 1997;89(1):297–306.

    CAS  PubMed  Google Scholar 

  51. Senechal K, et al. The CRKL adaptor protein transforms fibroblasts and functions in transformation by the BCR-ABL oncogene. J Biol Chem. 1996;271(38):23255–61.

    Article  CAS  PubMed  Google Scholar 

  52. Kipreos ET, et al. Cell cycle-regulated binding of c-Abl tyrosine kinase to DNA. Science. 1992;256(5055):382–5.

    Article  CAS  PubMed  Google Scholar 

  53. Goga A, et al. p53 dependent growth suppression by the c-Abl nuclear tyrosine kinase. Oncogene. 1995;11(4):791–9.

    CAS  PubMed  Google Scholar 

  54. Van Etten RA, et al. The COOH terminus of the c-Abl tyrosine kinase contains distinct F- and G-actin binding domains with bundling activity. J Cell Biol. 1994;124(3):325–40.

    Article  PubMed  Google Scholar 

  55. Renshaw MW, et al. The human leukemia oncogene bcr-abl abrogates the anchorage requirement but not the growth factor requirement for proliferation. Mol Cell Biol. 1995;15(3):1286–93.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Greuber EK, et al. Role of ABL family kinases in cancer: from leukaemia to solid tumours. Nat Rev Cancer. 2013;13(8):559–71.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Aman J, et al. Effective treatment of edema and endothelial barrier dysfunction with imatinib. Circulation. 2012;126(23):2728–38.

    Article  CAS  PubMed  Google Scholar 

  58. Dudek SM, et al. Abl tyrosine kinase phosphorylates nonmuscle Myosin light chain kinase to regulate endothelial barrier function. Mol Biol Cell. 2010;21(22):4042–56.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Clark BR, et al. Cell adhesion in the stromal regulation of haemopoiesis. Baillieres Clin Haematol. 1992;5(3):619–52.

    Article  CAS  PubMed  Google Scholar 

  60. Vigneri P, et al. Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat Med. 2001;7(2):228–34.

    Article  CAS  PubMed  Google Scholar 

  61. Gishizky ML, et al. Initiation of deregulated growth of multipotent progenitor cells by bcr-abl in vitro. Science. 1992;256(5058):836–9.

    Article  CAS  PubMed  Google Scholar 

  62. Daley GQ, et al. Transformation of an interleukin 3-dependent hematopoietic cell line by the chronic myelogenous leukemia-specific P210bcr/abl protein. Proc Natl Acad Sci U S A. 1988;85(23):9312–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Hariharan IK, et al. bcr-abl oncogene renders myeloid cell line factor independent: potential autocrine mechanism in chronic myeloid leukemia. Oncogene Res. 1988;3(4):387–99.

    CAS  PubMed  Google Scholar 

  64. Laneuville P, et al. Expression of the chronic myelogenous leukemia-associated p210bcr/abl oncoprotein in a murine IL-3 dependent myeloid cell line. Oncogene. 1991;6(2):275–82.

    CAS  PubMed  Google Scholar 

  65. Lugo TG, et al. The BCR-ABL oncogene transforms Rat-1 cells and cooperates with v-myc. Mol Cell Biol. 1989;9(3):1263–70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Daley GQ, et al. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990;247(4944):824–30.

    Article  CAS  PubMed  Google Scholar 

  67. Elefanty AG, et al. bcr-abl, the hallmark of chronic myeloid leukaemia in man, induces multiple haemopoietic neoplasms in mice. EMBO J. 1990;9(4):1069–78.

    PubMed Central  CAS  PubMed  Google Scholar 

  68. Kelliher MA, et al. Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL. Proc Natl Acad Sci U S A. 1990;87(17)):6649–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Hariharan IK. A bcr-v-abl oncogene induces lymphomas in transgenic mice. Mol Cell Biol. 1989;9(7):2798–805.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Honda H, et al. Expression of p210bcr/abl by metallothionein promoter induced T-cell leukemia in transgenic mice. Blood. 1995;85(10):2853–61.

    CAS  PubMed  Google Scholar 

  71. Honda H, et al. Development of acute lymphoblastic leukemia and myeloproliferative disorder in transgenic mice expressing p210bcr/abl: a novel transgenic model for human Ph1-positive leukemias. Blood. 1998;91(6):2067–75.

    CAS  PubMed  Google Scholar 

  72. Lancet JE, et al. Farnesyltransferase inhibitors in hematologic malignancies: new horizons in therapy. Blood. 2003;102(12):3880–9.

    Article  CAS  PubMed  Google Scholar 

  73. Morgan MA, et al. Therapeutic efficacy of prenylation inhibitors in the treatment of myeloid leukemia. Leukemia. 2003;17(8):1482–98.

    Article  CAS  PubMed  Google Scholar 

  74. Ravandi F, et al. Modulation of cellular signaling pathways: prospects for targeted therapy in hematological malignancies. Clin Cancer Res. 2003;9(2):535–50.

    CAS  PubMed  Google Scholar 

  75. Mizuki M, et al. Oncogenic receptor tyrosine kinase in leukemia. Cell Mol Biol. 2003;49(6):907–22.

    CAS  PubMed  Google Scholar 

  76. Sonoyama J, et al. Functional cooperation among Ras, STAT5, and phosphatidylinositol 3-kinase is required for full oncogenic activities of BCR/ABL in K562 cells. J Biol Chem. 2002;277(10):8076–82.

    Article  CAS  PubMed  Google Scholar 

  77. Matsumura I, et al. Roles for deregulated receptor tyrosine kinases and their downstream signaling molecules in hematologic malignancies. Cancer Sci. 2008;99(3):479–85.

    Article  CAS  PubMed  Google Scholar 

  78. Skorski T, et al. Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells. Blood. 1995;86(2):726–36.

    CAS  PubMed  Google Scholar 

  79. Sillaber C, et al. Evaluation of antileukaemic effects of rapamycin in patients with imatinib-resistant chronic myeloid leukaemia. Eur J Clin Invest. 2008;38(1):43–52.

    Article  CAS  PubMed  Google Scholar 

  80. Carayol N, et al. Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. Proc Natl Acad Sci U S A. 2010;107(28):12469–74.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Airiau K, et al. PI3K/mTOR pathway inhibitors sensitize chronic myeloid leukemia stem cells to nilotinib and restore the response of progenitors to nilotinib in the presence of stem cell factor. Cell Death Dis. 2013;4, e827.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Ding J, et al. Inhibition of PI3K/mTOR overcomes nilotinib resistance in BCR-ABL1 positive leukemia cells through translational down-regulation of MDM2. PLoS One. 2013;8(12), e83510.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  83. Naka K, et al. TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature. 2010;463(7281):676–80.

    Article  CAS  PubMed  Google Scholar 

  84. Pellicano F, et al. The antiproliferative activity of kinase inhibitors in chronic myeloid leukemia cells is mediated by FOXO transcription factors. Stem Cells. 2014;32(9):2324–37.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. Rane SG, Reddy EP. JAKs, STATs and Src kinases in hematopoiesis. Oncogene. 2002;21(21):3334–58.

    Article  CAS  PubMed  Google Scholar 

  86. Darnell Jr JE. STATs and gene regulation. Science. 1997;277(5532):1630–5.

    Article  CAS  PubMed  Google Scholar 

  87. Teglund S, et al. Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell. 1998;93(5):841–50.

    Article  CAS  PubMed  Google Scholar 

  88. Schepers H, et al. STAT5 is required for long-term maintenance of normal and leukemic human stem/progenitor cells. Blood. 2007;110(8):2880–8.

    Article  CAS  PubMed  Google Scholar 

  89. Nieborowska-Skorska M, et al. Signal transducer and activator of transcription (STAT)5 activation by BCR/ABL is dependent on intact Src homology (SH)3 and SH2 domains of BCR/ABL and is required for leukemogenesis. J Exp Med. 1999;189(8):1229–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  90. de Groot RP, et al. STAT5 activation by BCR-Abl contributes to transformation of K562 leukemia cells. Blood. 1999;94(3):1108–12.

    PubMed  Google Scholar 

  91. Sillaber C, et al. STAT5 activation contributes to growth and viability in Bcr/Abl-transformed cells. Blood. 2000;95(6):2118–25.

    CAS  PubMed  Google Scholar 

  92. Schaller-Schönitz M, et al. BCR-ABL affects STAT5A and STAT5B differentially. PLoS One. 2014;9(5), e97243.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  93. Sattler M, et al. The phosphatidylinositol polyphosphate 5-phosphatase SHIP and the protein tyrosine phosphatase SHP-2 form a complex in hematopoietic cells which can be regulated by BCR/ABL and growth factors. Oncogene. 1997;15(19):2379–84.

    Article  CAS  PubMed  Google Scholar 

  94. Scherr M, et al. Enhanced sensitivity to inhibition of SHP2, STAT5, and Gab2 expression in chronic myeloid leukemia (CML). Blood. 2006;107(8):3279–87.

    Article  CAS  PubMed  Google Scholar 

  95. Chen J, et al. SHP-2 phosphatase is required for hematopoietic cell transformation by Bcr-Abl. Blood. 2007;109(2):778–85.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. Sha F, et al. Dissection of the BCR-ABL signaling network using highly specific monobody inhibitors to the SHP2 SH2 domains. Proc Natl Acad Sci U S A. 2013;110(37):14924–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  97. Pendergast AM, et al. BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Cell. 1993;75(1):175–85.

    Article  CAS  PubMed  Google Scholar 

  98. Sattler M, et al. Critical role for Gab2 in transformation by BCR/ABL. Cancer Cell. 2002;1(5):479–92.

    Article  CAS  PubMed  Google Scholar 

  99. Wöhrle FU, et al. Gab2 signaling in chronic myeloid leukemia cells confers resistance to multiple Bcr-Abl inhibitors. Leukemia. 2013;27(1):118–29.

    Article  PubMed  CAS  Google Scholar 

  100. Barber DL, et al. Erythropoietin and interleukin-3 activate tyrosine phosphorylation of CBL and association with CRK adaptor proteins. Blood. 1997;89(9):3166–74.

    CAS  PubMed  Google Scholar 

  101. Gesbert F, et al. Interleukin-2 stimulation induces tyrosine phosphorylation of p120-Cbl and CrkL and formation of multimolecular signaling complexes in T lymphocytes and natural killer cells. J Biol Chem. 1988;273(7):3986–93.

    Article  Google Scholar 

  102. Odai H, et al. The proto-oncogene product c-Cbl becomes tyrosine phosphorylated by stimulation with GM-CSF or Epo and constitutively binds to the SH3 domain of Grb2/Ash in human hematopoietic cells. J Biol Chem. 1995;270(18):10800–5.

    Article  CAS  PubMed  Google Scholar 

  103. Wisniewski D, et al. c-kit ligand stimulates tyrosine phosphorylation of the c-Cbl protein in human hematopoietic cells. Leukemia. 1996;10(9):1436–42.

    CAS  PubMed  Google Scholar 

  104. Bhat A, et al. Interactions of CBL with BCR-ABL and CRKL in BCR-ABL-transformed myeloid cells. J Biol Chem. 1997;272(26):16170–5.

    Article  CAS  PubMed  Google Scholar 

  105. de Jong R, et al. CRKL is complexed with tyrosine-phosphorylated Cbl in Ph-positive leukemia. J Biol Chem. 1995;270(37):21468–71.

    Article  PubMed  Google Scholar 

  106. Pisick E, Xu G, Li JL, Prasad KV, Griffin JD. 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. 1996;12(4):839–46.

    PubMed  Google Scholar 

  107. Tari AM, Arlinghaus R, Lopez-Berestein G. Inhibition of Grb2 and Crkl proteins results in growth inhibition of Philadelphia chromosome positive leukemic cells. Biochem Biophys Res Commun. 1997;235(2):383–8.

    Article  CAS  PubMed  Google Scholar 

  108. Sakai R, et al. A novel signaling molecule, p130, forms stable complexes in vivo with v-Crk and v-Src in a tyrosine phosphorylation-dependent manner. EMBO J. 1994;13(16):3748–56.

    PubMed Central  CAS  PubMed  Google Scholar 

  109. Nojima Y, et al. Integrin-mediated cell adhesion promotes tyrosine phosphorylation of p130Cas, a Src homology 3-containing molecule having multiple Src homology 2-binding motifs. J Biol Chem. 1995;270(25):15398–402.

    Article  CAS  PubMed  Google Scholar 

  110. Harte MT, et al. p130Cas, a substrate associated with v-Src and v-Crk, localizes to focal adhesions and binds to focal adhesion kinase. J Biol Chem. 1996;271(23):13649–55.

    Article  CAS  PubMed  Google Scholar 

  111. Salgia R, et al. p130CAS forms a signaling complex with the adaptor protein CRKL in hematopoietic cells. J Biol Chem. 1996;271(41):25198–203.

    Article  CAS  PubMed  Google Scholar 

  112. Erpel T, et al. Src family protein tyrosine kinases and cellular signal transduction pathways. Curr Opin Cell Biol. 1995;7(2):176–82.

    Article  CAS  PubMed  Google Scholar 

  113. Odajima J, et al. Full oncogenic activities of v-Src are mediated by multiple signaling pathways Ras as an essential mediator for cell survival. J Biol Chem. 2000;275(31):24096–105.

    CAS  PubMed  Google Scholar 

  114. Chaturvedi P, et al. Abrogation of interleukin-3 dependence of myeloid cells by the v-src oncogene requires SH2 and SH3 domains which specify activation of STATs. Mol Cell Biol. 1997;17(6):3295–304.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  115. Guan JL, et al. Regulation of focal adhesion-associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation. Nature. 1992;358(6388):690–2.

    Article  CAS  PubMed  Google Scholar 

  116. Nori M, et al. Inhibition of v-src-induced transformation by a GTPase-activating protein. Mol Cell Biol. 1991;11(5):2812–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  117. Aftab DT, et al. Ras-independent transformation by v-Src. Proc Natl Acad Sci U S A. 1997;94(7):3028–33.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  118. DeClue JE, et al. Suppression of src transformation by overexpression of full-length GTPase-activating protein (GAP) or of the GAP C terminus. Mol Cell Biol. 1991;11(5):2819–25.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  119. Oldham SM, et al. Ras, but not Src, transformation of RIE-1 epithelial cells is dependent on activation of the mitogen-activated protein kinase cascade. Oncogene. 1998;16(20):2565–73.

    Article  CAS  PubMed  Google Scholar 

  120. Wu J, et al. Association between imatinib-resistant BCR-ABL mutation-negative leukemia and persistent activation of LYN kinase. J Natl Cancer Inst. 2008;100(13):926–39.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  121. Pene-Dumitrescu T, et al. Expression of a Src family kinase in chronic myelogenous leukemia cells induces resistance to imatinib in a kinase-dependent manner. J Biol Chem. 2010;285(28):21446–57.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  122. Wu J, et al. Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells. Blood. 2008;111(7):3821–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  123. Parganas E, et al. Jak2 is essential for signaling through a variety of cytokine receptors. Cell. 1998;93(3):385–95.

    Article  CAS  PubMed  Google Scholar 

  124. Neubauer H, et al. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell. 1998;93(3):397–409.

    Article  CAS  PubMed  Google Scholar 

  125. Park SO, et al. Conditional deletion of Jak2 reveals an essential role in hematopoiesis throughout mouse ontogeny: implications for Jak2 inhibition in humans. PLoS One. 2013;8(3), e59675.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  126. Grisouard J, et al. Selective deletion of Jak2 in adult mouse hematopoietic cells leads to lethal anemia and thrombocytopenia. Haematologica. 2014;99(4):e52–4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  127. Jiang X, et al. Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies. Leukemia. 2007;21(5):926–35.

    CAS  PubMed  Google Scholar 

  128. Zhou LL, et al. AHI-1 interacts with BCR-ABL and modulates BCR-ABL transforming activity and imatinib response of CML stem/progenitor cells. J Exp Med. 2008;205(11):2657–71.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  129. Liu X, et al. Molecular and structural characterization of the SH3 domain of AHI-1 in regulation of cellular resistance of BCR-ABL(+) chronic myeloid leukemia cells to tyrosine kinase inhibitors. Proteomics. 2012;12(13):2094–106.

    Article  CAS  PubMed  Google Scholar 

  130. Chen M, et al. Targeting primitive chronic myeloid leukemia cells by effective inhibition of a new AHI-1-BCR-ABL-JAK2 complex. J Natl Cancer Inst. 2013;105:405–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  131. Lin H, et al. Selective JAK2/ABL dual inhibition therapy effectively eliminates TKI-insensitive CML stem/progenitor cells. Oncotarget. 2014;5(18):8637–50.

    Article  PubMed Central  PubMed  Google Scholar 

  132. Reya T, et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature. 2003;423:409–14.

    Article  CAS  PubMed  Google Scholar 

  133. Baba Y, et al. Constitutively active β-catenin confers multilineage differentiation potential on lymphoid and myeloid progenitors. Immunity. 2005;23:599–609.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  134. Coluccia AM, et al. Bcr-Abl stabilizes β-catenin in chronic myeloid leukemia through its tyrosine phosphorylation. EMBO J. 2007;26:1456–66.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  135. Abrahamsson AE, et al. Glycogen synthase kinase 3β missplicing contributes to leukemia stem cell generation. Proc Natl Acad Sci U S A. 2009;106(10):3925–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  136. Zhang B, et al. Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt-β-catenin signaling. Blood. 2013;121(10):1824–38.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  137. Zhao C, Blum J, Chen A, et al. Loss of β-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell. 2007;12(6):528–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  138. Reddiconto G, et al. Targeting of GSK3β promotes imatinib-mediated apoptosis in quiescent CD34+ chronic myeloid leukemia progenitors, preserving normal stem cells. Blood. 2012;119(10):2335–45.

    Article  CAS  PubMed  Google Scholar 

  139. Jamieson CH, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 2004;351(7):657–67.

    Article  CAS  PubMed  Google Scholar 

  140. Zhao C, Chen A, Jamieson CH, et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature. 2009;458(7239):776–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  141. Cea M, et al. Tracking molecular relapse of chronic myeloid leukemia by measuring Hedgehog signaling status. Leuk Lymphoma. 2013;54(2):342–52.

    Article  CAS  PubMed  Google Scholar 

  142. Sengupta A, et al. Deregulation and cross talk among Sonic hedgehog, Wnt, Hox and Notch signaling in chronic myeloid leukemia progression. Leukemia. 2007;21(5):949–55.

    CAS  PubMed  Google Scholar 

  143. Su W, et al. Sonic hedgehog maintains survival and growth of chronic myeloid leukemia progenitor cells through b-catenin signaling. Exp Hematol. 2012;40(5):418–27.

    Article  CAS  PubMed  Google Scholar 

  144. Dierks C, Beigi R, Guo GR, et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell. 2008;14:238–49.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology and Rheumatology, Kinki University, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan

    Itaru Matsumura

Authors
  1. Itaru Matsumura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Itaru Matsumura .

Editor information

Editors and Affiliations

  1. Department of Hematology, Saitama Medical Center Saitama MEdical University, Kawagoe, Saitama, Japan

    Masahiro Kizaki

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Japan

About this chapter

Cite this chapter

Matsumura, I. (2016). Roles for Signaling Molecules in the Growth and Survival of CML Cells. In: Kizaki, M. (eds) Molecular Pathogenesis and Treatment of Chronic Myelogenous Leukemia. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55714-2_3

Download citation

  • DOI: https://doi.org/10.1007/978-4-431-55714-2_3

  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-55713-5

  • Online ISBN: 978-4-431-55714-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation