Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Spotlight Review
  • Published:

Comparison of mutated ABL1 and JAK2 as oncogenes and drug targets in myeloproliferative disorders

Leukemia volume 22, pages 1320–1334 (2008)Cite this article

Abstract

Constitutively activated mutants of the non-receptor tyrosine kinases (TK) ABL1 (Abelson murine leukemia viral (v-abl) homolog (1) protein) and JAK2 (JAnus Kinase 2 or Just Another Kinase 2) play a central role in the pathogenesis of clinically and morphologically distinct chronic myeloproliferative disorders but are also found in some cases of de novo acute leukemia and lymphoma. Ligand-independent activation occurs as a consequence of point mutations or insertions/deletions within functionally relevant regulatory domains (JAK2) or the creation of TK fusion proteins by balanced reciprocal translocations, insertions or episomal amplification (ABL1 and JAK2). Specific abnormalities are correlated with clinical phenotype, although some are broad and encompass several World Health Organization-defined entities. TKs are excellent drug targets as exemplified by the activity of imatinib in BCR-ABL1-positive disease, particularly chronic myeloid leukemia. Resistance to imatinib is seen in a minority of cases and is often associated with the appearance of secondary point mutations within the TK domain of BCR-ABL1. These mutations are highly variable in their sensitivity to increased doses of imatinib or alternative TK inhibitors such as nilotinib or dasatinib. Selective and non-selective inhibitors of JAK2 are currently being developed, and encouraging data from pre-clinical experiments and initial phase-I studies regarding efficacy and potential toxicity of these compounds have already been reported.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Dameshek W . Some speculations on the myeloproliferative syndromes. Blood 1951; 6: 372–375.

    CAS  PubMed  Google Scholar 

  2. Vardiman JW, Harris NL, Brunning RD . The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002; 100: 2292–2302.

    CAS  PubMed  Google Scholar 

  3. Tefferi A . The history of myeloproliferative disorders: before and after Dameshek. Leukemia 2008; 22: 3–13.

    CAS  PubMed  Google Scholar 

  4. Nowell PC, Hungerford DA . Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst 1960; 25: 85–109.

    CAS  PubMed  Google Scholar 

  5. Rowley JD . Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973; 243: 290–293.

    CAS  PubMed  Google Scholar 

  6. Daley GQ, Van Etten RA, Baltimore D . Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 1990; 247: 824–830.

    Article  CAS  PubMed  Google Scholar 

  7. Daley GQ, Van Etten RA, Baltimore D . Blast crisis in a murine model of chronic myelogenous leukemia. Proc Natl Acad Sci USA 1991; 88: 11335–11338.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Ben-Neriah Y, Daley GQ, Mes-Masson AM, Witte ON, Baltimore D . The chronic myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrid gene. Science 1986; 233: 212–214.

    CAS  PubMed  Google Scholar 

  9. McLaughlin J, Chianese E, Witte ON . In vitro transformation of immature hematopoietic cells by the P210 BCR/ABL oncogene product of the Philadelphia chromosome. Proc Natl Acad Sci USA 1987; 84: 6558–6562.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Reiter A, Walz C, Cross NCP . Tyrosine kinases as therapeutic targets in BCR-ABL negative chronic myeloproliferative disorders. Curr Drug Targets 2007; 8: 205–216.

    CAS  PubMed  Google Scholar 

  11. Vizmanos JL, Hernandez R, Vidal MJ, Larrayoz MJ, Odero MD, Marin J et al. Clinical variability of patients with the t(6;8)(q27;p12) and FGFR1OP-FGFR1 fusion: two further cases. Hematol J 2004; 5: 534–537.

    CAS  PubMed  Google Scholar 

  12. James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 434: 1144–1148.

    CAS  PubMed  Google Scholar 

  13. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005; 352: 1779–1790.

    Article  CAS  PubMed  Google Scholar 

  14. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005; 7: 387–397.

    Article  CAS  PubMed  Google Scholar 

  15. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365: 1054–1061.

    CAS  PubMed  Google Scholar 

  16. Zhao R, Xing S, Li Z, Fu X, Li Q, Krantz SB et al. Identification of an acquired JAK2 mutation in Polycythemia vera. J Biol Chem 2005; 280: 22788–22792.

    CAS  PubMed  Google Scholar 

  17. Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007; 356: 459–468.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA, Wadleigh M et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 2006; 108: 3472–3476.

    Article  CAS  PubMed  Google Scholar 

  19. Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 2006; 3: e270.

    PubMed  PubMed Central  Google Scholar 

  20. Krause DS, Van Etten RA . Tyrosine kinases as targets for cancer therapy. N Engl J Med 2005; 353: 172–187.

    CAS  PubMed  Google Scholar 

  21. Wetzler M, Talpaz M, Van Etten RA, Hirsh-Ginsberg C, Beran M, Kurzrock R . Subcellular localization of Bcr, Abl, and Bcr-Abl proteins in normal and leukemic cells and correlation of expression with myeloid differentiation. J Clin Invest 1993; 92: 1925–1939.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Behrmann I, Smyczek T, Heinrich PC, Schmitz-Van de LH, Komyod W, Giese B et al. Janus kinase (Jak) subcellular localization revisited: the exclusive membrane localization of endogenous Janus kinase 1 by cytokine receptor interaction uncovers the Jak.receptor complex to be equivalent to a receptor tyrosine kinase. J Biol Chem 2004; 279: 35486–35493.

    CAS  PubMed  Google Scholar 

  23. Lobie PE, Ronsin B, Silvennoinen O, Haldosen LA, Norstedt G, Morel G . Constitutive nuclear localization of Janus kinases 1 and 2. Endocrinology 1996; 137: 4037–4045.

    CAS  PubMed  Google Scholar 

  24. Wen ST, Jackson PK, Van Etten RA . The cytostatic function of c-Abl is controlled by multiple nuclear localization signals and requires the p53 and Rb tumor suppressor gene products. EMBO J 1996; 15: 1583–1595.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Taagepera S, McDonald D, Loeb JE, Whitaker LL, McElroy AK, Wang JY et al. Nuclear-cytoplasmic shuttling of C-ABL tyrosine kinase. Proc Natl Acad Sci USA 1998; 95: 7457–7462.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Van Etten RA . Cycling, stressed-out and nervous: cellular functions of c-Abl. Trends Cell Biol 1999; 9: 179–186.

    CAS  PubMed  Google Scholar 

  27. Yoshida K, Miki Y . Enabling death by the Abl tyrosine kinase: mechanisms for nuclear shuttling of c-Abl in response to DNA damage. Cell Cycle 2005; 4: 777–779.

    CAS  PubMed  Google Scholar 

  28. Yoshida K . Regulation for nuclear targeting of the Abl tyrosine kinase in response to DNA damage. Adv Exp Med Biol 2007; 604: 155–165.

    PubMed  Google Scholar 

  29. Wen ST, Van Etten RA . 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: 2456–2467.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Welch PJ, Wang JY . Abrogation of retinoblastoma protein function by c-Abl through tyrosine kinase-dependent and -independent mechanisms. Mol Cell Biol 1995; 15: 5542–5551.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Sawyers CL, McLaughlin J, Goga A, Havlik M, Witte O . The nuclear tyrosine kinase c-Abl negatively regulates cell growth. Cell 1994; 77: 121–131.

    CAS  PubMed  Google Scholar 

  32. Wang JY . Abl tyrosine kinase in signal transduction and cell-cycle regulation. Curr Opin Genet Dev 1993; 3: 35–43.

    CAS  PubMed  Google Scholar 

  33. Schwartzberg PL, Stall AM, Hardin JD, Bowdish KS, Humaran T, Boast S et al. Mice homozygous for the ablm1 mutation show poor viability and depletion of selected B and T cell populations. Cell 1991; 65: 1165–1175.

    CAS  PubMed  Google Scholar 

  34. Kharbanda S, Pandey P, Morris PL, Whang Y, Xu Y, Sawant S et al. Functional role for the c-Abl tyrosine kinase in meiosis I. Oncogene 1998; 16: 1773–1777.

    CAS  PubMed  Google Scholar 

  35. Tybulewicz VL, Crawford CE, Jackson PK, Bronson RT, Mulligan RC . Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 1991; 65: 1153–1163.

    CAS  PubMed  Google Scholar 

  36. Ching YP, Qi Z, Wang JH . Cloning of three novel neuronal Cdk5 activator binding proteins. Gene 2000; 242: 285–294.

    CAS  PubMed  Google Scholar 

  37. Hardin JD, Boast S, Schwartzberg PL, Lee G, Alt FW, Stall AM et al. Bone marrow B lymphocyte development in c-abl-deficient mice. Cell Immunol 1995; 165: 44–54.

    CAS  PubMed  Google Scholar 

  38. Hardin JD, Boast S, Schwartzberg PL, Lee G, Alt FW, Stall AM et al. Abnormal peripheral lymphocyte function in c-abl mutant mice. Cell Immunol 1996; 172: 100–107.

    CAS  PubMed  Google Scholar 

  39. Nagar B, Hantschel O, Young MA, Scheffzek K, Veach D, Bornmann V et al. Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell 2003; 112: 859–871.

    CAS  PubMed  Google Scholar 

  40. Pluk H, Dorey K, Superti-Furga G . Autoinhibition of c-Abl. Cell 2002; 108: 247–259.

    CAS  PubMed  Google Scholar 

  41. Van Etten RA . c-Abl regulation: a tail of two lipids. Curr Biol 2003; 13: R608–R610.

    CAS  PubMed  Google Scholar 

  42. Plattner R, Irvin BJ, Guo S, Blackburn K, Kazlauskas A, Abraham RT et al. A new link between the c-Abl tyrosine kinase and phosphoinositide signalling through PLC-gamma1. Nat Cell Biol 2003; 5: 309–319.

    CAS  PubMed  Google Scholar 

  43. Arlinghaus RB . Bcr: a negative regulator of the Bcr-Abl oncoprotein in leukemia. Oncogene 2002; 21: 8560–8567.

    CAS  PubMed  Google Scholar 

  44. Saharinen P, Takaluoma K, Silvennoinen O . Regulation of the Jak2 tyrosine kinase by its pseudokinase domain. Mol Cell Biol 2000; 20: 3387–3395.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Ma AC, Ward AC, Liang R, Leung AY . The role of jak2a in zebrafish hematopoiesis. Blood 2007; 110: 1824–1830.

    CAS  PubMed  Google Scholar 

  46. Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S et al. Jak2 is essential for signaling through a variety of cytokine receptors. Cell 1998; 93: 385–395.

    CAS  PubMed  Google Scholar 

  47. Funakoshi-Tago M, Pelletier S, Matsuda T, Parganas E, Ihle JN . Receptor specific downregulation of cytokine signaling by autophosphorylation in the FERM domain of Jak2. EMBO J 2006; 25: 4763–4772.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Kazansky AV, Kabotyanski EB, Wyszomierski SL, Mancini MA, Rosen JM . Differential effects of prolactin and src/abl kinases on the nuclear translocation of STAT5B and STAT5A. J Biol Chem 1999; 274: 22484–22492.

    CAS  PubMed  Google Scholar 

  49. Meyer T, Vinkemeier U . STAT nuclear translocation: potential for pharmacological intervention. Expert Opin Ther Targets 2007; 11: 1355–1365.

    CAS  PubMed  Google Scholar 

  50. Ilaria Jr RL, Van Etten RA . P210 and P190(BCR/ABL) induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members. J Biol Chem 1996; 271: 31704–31710.

    CAS  PubMed  Google Scholar 

  51. Xie S, Wang Y, Liu J, Sun T, Wilson MB, Smithgall TE et al. Involvement of Jak2 tyrosine phosphorylation in Bcr-Abl transformation. Oncogene 2001; 20: 6188–6195.

    CAS  PubMed  Google Scholar 

  52. Samanta AK, Lin H, Sun T, Kantarjian H, Arlinghaus RB . Janus kinase 2: a critical target in chronic myelogenous leukemia. Cancer Res 2006; 66: 6468–6472.

    CAS  PubMed  Google Scholar 

  53. Wernig G, Mercher T, Okabe R, Levine RL, Lee BH, Gilliland DG . Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood 2006; 107: 4274–4281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Schwaller J, Frantsve J, Aster J, Williams IR, Tomasson MH, Ross TS et al. Transformation of hematopoietic cell lines to growth-factor independence and induction of a fatal myelo- and lymphoproliferative disease in mice by retrovirally transduced TEL/JAK2 fusion genes. EMBO J 1998; 17: 5321–5333.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Schwaller J, Parganas E, Wang D, Cain D, Aster JC, Williams IR et al. Stat5 is essential for the myelo- and lymphoproliferative disease induced by TEL/JAK2. Mol Cell 2000; 6: 693–704.

    CAS  PubMed  Google Scholar 

  56. Barnes DJ, Melo JV . Cytogenetic and molecular genetic aspects of chronic myeloid leukaemia. Acta Haematol 2002; 108: 180–202.

    CAS  PubMed  Google Scholar 

  57. Pane F, Frigeri F, Sindona M, Luciano L, Ferrara F, Cimino R et al. Neutrophilic-chronic myeloid leukemia: a distinct disease with a specific molecular marker (BCR/ABL with C3/A2 junction). Blood 1996; 88: 2410–2414.

    CAS  PubMed  Google Scholar 

  58. Calabretta B, Perrotti D . The biology of CML blast crisis. Blood 2004; 103: 4010–4022.

    CAS  PubMed  Google Scholar 

  59. Klejman A, Schreiner SJ, Nieborowska-Skorska M, Slupianek A, Wilson M, Smithgall TE et al. The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells. EMBO J 2002; 21: 5766–5774.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Xie S, Lin H, Sun T, Arlinghaus RB . Jak2 is involved in c-Myc induction by Bcr-Abl. Oncogene 2002; 21: 7137–7146.

    CAS  PubMed  Google Scholar 

  61. Nosaka T, Kawashima T, Misawa K, Ikuta K, Mui AL, Kitamura T . STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells. EMBO J 1999; 18: 4754–4765.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Sattler M, Mohi MG, Pride YB, Quinnan LR, Malouf NA, Podar K et al. Critical role for Gab2 in transformation by BCR/ABL. Cancer Cell 2002; 1: 479–492.

    CAS  PubMed  Google Scholar 

  63. Neviani P, Santhanam R, Trotta R, Notari M, Blaser BW, Liu S et al. The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein. Cancer Cell 2005; 8: 355–368.

    CAS  PubMed  Google Scholar 

  64. Graux C, Cools J, Melotte C, Quentmeier H, Ferrando A, Levine R et al. Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Nat Genet 2004; 36: 1084–1089.

    CAS  PubMed  Google Scholar 

  65. Burmeister T, Gokbuget N, Reinhardt R, Rieder H, Hoelzer D, Schwartz S . NUP214-ABL1 in adult T-ALL: the GMALL study group experience. Blood 2006; 108: 3556–3559.

    CAS  PubMed  Google Scholar 

  66. De Keersmaecker K, Graux C, Odero MD, Mentens N, Somers R, Maertens J et al. Fusion of EML1 to ABL1 in T-cell acute lymphoblastic leukemia with cryptic t(9;14)(q34;q32). Blood 2005; 105: 4849–4852.

    CAS  PubMed  Google Scholar 

  67. Andreasson P, Johansson B, Carlsson M, Jarlsfelt I, Fioretos T, Mitelman F et al. BCR/ABL-negative chronic myeloid leukemia with ETV6/ABL fusion. Genes Chromosomes Cancer 1997; 20: 299–304.

    CAS  PubMed  Google Scholar 

  68. Million RP, Aster J, Gilliland DG, Van Etten RA . The Tel-Abl (ETV6-Abl) tyrosine kinase, product of complex (9;12) translocations in human leukemia, induces distinct myeloproliferative disease in mice. Blood 2002; 99: 4568–4577.

    CAS  PubMed  Google Scholar 

  69. Soler G, Radford-Weiss I, Ben-Abdelali R, Mahlaoui N, Ponceau JF, Macintyre EA et al. Fusion of ZMIZ1 to ABL1 in a B-cell acute lymphoblastic leukaemia with a t(9;10)(q34;q22.3) translocation. Leukemia 2008; (in press).

  70. De Braekeleer E, Douet-Guilbert N, Le Bris MJ, Berthou C, Morel F, De BM . A new partner gene fused to ABL1 in a t(1;9)(q24;q34)-associated B-cell acute lymphoblastic leukemia. Leukemia 2007; 21: 2220–2221.

    CAS  PubMed  Google Scholar 

  71. Heisterkamp N, Stephenson JR, Groffen J, Hansen PF, de Klein A, Bartram CR et al. Localization of the c-ab1 oncogene adjacent to a translocation break point in chronic myelocytic leukaemia. Nature 1983; 306: 239–242.

    CAS  PubMed  Google Scholar 

  72. Reiter A, Walz C, Watmore A, Schoch C, Blau I, Schlegelberger B et al. The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2. Cancer Res 2005; 65: 2662–2667.

    CAS  PubMed  Google Scholar 

  73. Corvi R, Berger N, Balczon R, Romeo G . RET/PCM-1: a novel fusion gene in papillary thyroid carcinoma. Oncogene 2000; 19: 4236–4242.

    CAS  PubMed  Google Scholar 

  74. Bousquet M, Quelen C, De MV, Duchayne E, Roquefeuil B, Delsol G et al. The t(8;9)(p22;p24) translocation in atypical chronic myeloid leukaemia yields a new PCM1-JAK2 fusion gene. Oncogene 2005; 24: 7248–7252.

    CAS  PubMed  Google Scholar 

  75. Murati A, Gelsi-Boyer V, Adelaide J, Perot C, Talmant P, Giraudier S et al. PCM1-JAK2 fusion in myeloproliferative disorders and acute erythroid leukemia with t(8;9) translocation. Leukemia 2005; 19: 1692–1696.

    CAS  PubMed  Google Scholar 

  76. Heiss S, Erdel M, Gunsilius E, Nachbaur D, Tzankov A . Myelodysplastic/myeloproliferative disease with erythropoietic hyperplasia (erythroid preleukemia) and the unique translocation (8;9)(p23;p24): first description of a case. Hum Pathol 2005; 36: 1148–1151.

    CAS  PubMed  Google Scholar 

  77. Adelaide J, Perot C, Gelsi-Boyer V, Pautas C, Murati A, Copie-Bergman C et al. A t(8;9) translocation with PCM1-JAK2 fusion in a patient with T-cell lymphoma. Leukemia 2006; 20: 536–537.

    CAS  PubMed  Google Scholar 

  78. Jones AV, Cross NC . Oncogenic derivatives of platelet-derived growth factor receptors. Cell Mol Life Sci 2004; 61: 2912–2923.

    CAS  PubMed  Google Scholar 

  79. Griesinger F, Podleschny M, Steffens R, Bohlander S, Woermann B, Haase D . A novel BCR-JAK2 fusion gene is the result of a translocation (9;22)(p24;q11) in a case of CML. Blood 2000; 96: 352a.

    Google Scholar 

  80. Peeters P, Raynaud SD, Cools J, Wlodarska I, Grosgeorge J, Philip P et al. Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia. Blood 1997; 90: 2535–2540.

    CAS  PubMed  Google Scholar 

  81. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293: 876–880.

    CAS  PubMed  Google Scholar 

  82. Hochhaus A, Kreil S, Corbin AS, La Rosee P, Muller MC, Lahaye T et al. Molecular and chromosomal mechanisms of resistance to imatinib (ST1571) therapy. Leukemia 2002; 16: 2190–2196.

    CAS  PubMed  Google Scholar 

  83. Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002; 2: 117–125.

    CAS  PubMed  Google Scholar 

  84. Branford S, Rudzki Z, Walsh S, Grigg A, Arthur C, Taylor K et al. High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood 2002; 99: 3472–3475.

    CAS  PubMed  Google Scholar 

  85. Branford S, Rudzki Z, Walsh S, Parkinson I, Grigg A, Szer J 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: 276–283.

    CAS  PubMed  Google Scholar 

  86. Apperley JF . Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 2007; 8: 1018–1029.

    CAS  PubMed  Google Scholar 

  87. Apperley JF . Part II: management of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 2007; 8: 1116–1128.

    CAS  PubMed  Google Scholar 

  88. Soverini S, Martinelli G, Rosti G, Bassi S, Amabile M, Poerio A et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J Clin Oncol 2005; 23: 4100–4109.

    CAS  PubMed  Google Scholar 

  89. Soverini S, Colarossi S, Gnani A, Rosti G, Castagnetti F, Poerio A et al. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res 2006; 12: 7374–7379.

    CAS  PubMed  Google Scholar 

  90. Dupont S, Masse A, James C, Teyssandier I, Lecluse Y, Larbret F et al. The JAK2 617V>F mutation triggers erythropoietin hypersensitivity and terminal erythroid amplification in primary cells from patients with polycythemia vera. Blood 2007; 110: 1013–1021.

    CAS  PubMed  Google Scholar 

  91. Tao WJ, Lin H, Sun T, Samanta AK, Arlinghaus R . BCR-ABL oncogenic transformation of NIH 3T3 fibroblasts requires the IL-3 receptor. Oncogene 2008; 27: 3194–3200.

    CAS  PubMed  Google Scholar 

  92. Lu X, Huang LJ, Lodish HF . Dimerization by a cytokine receptor is necessary for constitutive activation of JAK2V617F. J Biol Chem 2008; 283: 5258–5266.

    CAS  PubMed  Google Scholar 

  93. Zaleskas VM, Krause DS, Lazarides K, Patel N, Hu Y, Li S et al. Molecular pathogenesis and therapy of polycythemia induced in mice by JAK2 V617F. PLoS ONE 2006; 1: e18.

    PubMed  PubMed Central  Google Scholar 

  94. Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 2005; 106: 2162–2168.

    CAS  PubMed  Google Scholar 

  95. Steensma DP, Dewald GW, Lasho TL, Powell HL, McClure RF, Levine RL et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes. Blood 2005; 106: 1207–1209.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Wang SA, Hasserjian RP, Loew JM, Sechman EV, Jones D, Hao S et al. Refractory anemia with ringed sideroblasts associated with marked thrombocytosis harbors JAK2 mutation and shows overlapping myeloproliferative and myelodysplastic features. Leukemia 2006; 20: 1641–1644.

    PubMed  Google Scholar 

  97. Boissinot M, Garand R, Hamidou M, Hermouet S . The JAK2-V617F mutation and essential thrombocythemia features in a subset of patients with refractory anemia with ring sideroblasts (RARS). Blood 2006; 108: 1781–1782.

    CAS  PubMed  Google Scholar 

  98. Ceesay MM, Lea NC, Ingram W, Westwood NB, Gaken J, Mohamedali A et al. The JAK2 V617F mutation is rare in RARS but common in RARS-T. Leukemia 2006; 20: 2060–2061.

    CAS  PubMed  Google Scholar 

  99. Schmitt-Graeff AH, Teo SS, Olschewski M, Schaub F, Haxelmans S, Kirn A et al. JAK2V617F mutation status identifies subtypes of refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Haematologica 2008; 93: 34–40.

    CAS  PubMed  Google Scholar 

  100. Johan MF, Goodeve AC, Bowen DT, Frew ME, Reilly JT . JAK2 V617F Mutation is uncommon in chronic myelomonocytic leukaemia. Br J Haematol 2005; 130: 968.

    CAS  PubMed  Google Scholar 

  101. Frohling S, Lipka DB, Kayser S, Scholl C, Schlenk RF, Dohner H et al. Rare occurrence of the JAK2 V617F mutation in AML subtypes M5, M6, and M7. Blood 2006; 107: 1242–1243.

    PubMed  PubMed Central  Google Scholar 

  102. Karow A, Waller C, Reimann C, Niemeyer CM, Kratz CP . JAK2 mutations other than V617F: A novel mutation and mini review. Leuk Res 2008; 32: 365–366.

    CAS  PubMed  Google Scholar 

  103. Zhang SJ, Li JY, Li WD, Song JH, Xu W, Qiu HX . The investigation of JAK2 mutation in Chinese myeloproliferative diseases-identification of a novel C616Y point mutation in a PV patient. Int J Lab Hematol 2007; 29: 71–72.

    PubMed  Google Scholar 

  104. Kratz CP, Boll S, Kontny U, Schrappe M, Niemeyer CM, Stanulla M . Mutational screen reveals a novel JAK2 mutation, L611S, in a child with acute lymphoblastic leukemia. Leukemia 2006; 20: 381–383.

    CAS  PubMed  Google Scholar 

  105. Malinge S, Ben-Abdelali R, Settegrana C, Radford-Weiss I, Debre M, Beldjord K et al. Novel activating JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemia. Blood 2007; 109: 2202–2204.

    CAS  PubMed  Google Scholar 

  106. Lee JW, Kim YG, Soung YH, Han KJ, Kim SY, Rhim HS et al. The JAK2 V617F mutation in de novo acute myelogenous leukemias. Oncogene 2006; 25: 1434–1436.

    CAS  PubMed  Google Scholar 

  107. Grunebach F, Bross-Bach U, Kanz L, Brossart P . Detection of a new JAK2 D620E mutation in addition to V617F in a patient with polycythemia vera. Leukemia 2006; 20: 2210–2211.

    CAS  PubMed  Google Scholar 

  108. Schnittger S, Bacher U, Kern W, Schroder M, Haferlach T, Schoch C . Report on two novel nucleotide exchanges in the JAK2 pseudokinase domain: D620E and E627E. Leukemia 2006; 20: 2195–2197.

    CAS  PubMed  Google Scholar 

  109. Mercher T, Wernig G, Moore SA, Levine RL, Gu TL, Frohling S et al. JAK2T875N is a novel activating mutation that results in myeloproliferative disease with features of megakaryoblastic leukemia in a murine bone marrow transplantation model. Blood 2006; 108: 2770–2779.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Butcher CM, Hahn U, To LB, Gecz J, Wilkins EJ, Scott HS et al. Two novel JAK2 exon 12 mutations in JAK2V617F-negative polycythaemia vera patients. Leukemia 2008; 22: 870–873.

    CAS  PubMed  Google Scholar 

  111. Williams DM, Kim AH, Rogers O, Spivak JL, Moliterno AR . Phenotypic variations and new mutations in JAK2 V617F-negative polycythemia vera, erythrocytosis, and idiopathic myelofibrosis. Exp Hematol 2007; 35: 1641–1646.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Pietra D, Li S, Brisci A, Passamonti F, Rumi E, Theocharides A et al. Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders. Blood 2008; 111: 1686–1689.

    CAS  PubMed  Google Scholar 

  113. Staerk J, Kallin A, Demoulin JB, Vainchenker W, Constantinescu SN . JAK1 and Tyk2 activation by the homologous polycythemia vera JAK2 V617F mutation: cross-talk with IGF1 receptor. J Biol Chem 2005; 280: 41893–41899.

    CAS  PubMed  Google Scholar 

  114. Xiang Z, Zhao Y, Mitaksov V, Fremont DH, Kasai Y, Molitoris A et al. Identification of somatic JAK1 mutations in patients with acute myeloid leukemia. Blood 2008; 111: 4809–4812.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Inami M, Inokuchi K, Okabe M, Kosaka F, Mitamura Y, Yamaguchi H et al. Polycythemia associated with the JAK2V617F mutation emerged during treatment of chronic myelogenous leukemia. Leukemia 2007; 21: 1103–1104.

    CAS  PubMed  Google Scholar 

  116. Kramer A, Reiter A, Kruth J, Erben P, Hochhaus A, Muller M et al. JAK2-V617F mutation in a patient with Philadelphia-chromosome-positive chronic myeloid leukaemia. Lancet Oncol 2007; 8: 658–660.

    PubMed  Google Scholar 

  117. Hussein K, Bock O, Seegers A, Flasshove M, Henneke F, Buesche G et al. Myelofibrosis evolving during imatinib treatment of a chronic myeloproliferative disease with coexisting BCR-ABL translocation and JAK2V617F mutation. Blood 2007; 109: 4106–4107.

    CAS  PubMed  Google Scholar 

  118. Scott LM, Campbell PJ, Baxter EJ, Todd T, Stephens P, Edkins S et al. The V617F JAK2 mutation is uncommon in cancers and in myeloid malignancies other than the classic myeloproliferative disorders. Blood 2005; 106: 2920–2921.

    CAS  PubMed  Google Scholar 

  119. Hussein K, Bock O, Theophile K, Seegers A, Arps H, Basten O et al. Chronic myeloproliferative diseases with concurrent BCR-ABL junction and JAK2(V617F) mutation. Leukemia 2008; 22: 1059–1062.

    CAS  PubMed  Google Scholar 

  120. Bornhauser M, Mohr B, Oelschlaegel U, Bornhauser P, Jacki S, Ehninger G et al. Concurrent JAK2(V617F) mutation and BCR-ABL translocation within committed myeloid progenitors in myelofibrosis. Leukemia 2007; 21: 1824–1826.

    CAS  PubMed  Google Scholar 

  121. Illmer T, Schaich M, Ehninger G, Thiede C . Tyrosine kinase mutations of JAK2 are rare events in AML but influence prognosis of patients with CBF-leukemias. Haematologica 2007; 92: 137–138.

    PubMed  Google Scholar 

  122. Sotlar K, Bache A, Stellmacher F, Bultmann B, Valent P, Horny HP . Systemic mastocytosis associated with chronic idiopathic myelofibrosis: a distinct subtype of systemic mastocytosis-associated clonal hematological nonmast cell lineage disorder carrying the activating point mutations KITD816V and JAK2V617F. J Mol Diagn 2008; 10: 58–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Sidon P, El HH, Dessars B, Heimann P . The JAK2V617F mutation is detectable at very low level in peripheral blood of healthy donors. Leukemia 2006; 20: 1622.

    CAS  PubMed  Google Scholar 

  124. Xu X, Zhang Q, Luo J, Xing S, Li Q, Krantz SB et al. JAK2(V617F): Prevalence in a large Chinese hospital population. Blood 2007; 109: 339–342.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Bose S, Deininger M, Gora-Tybor J, Goldman JM, Melo JV . The presence of typical and atypical BCR-ABL fusion genes in leukocytes of normal individuals: biologic significance and implications for the assessment of minimal residual disease. Blood 1998; 92: 3362–3367.

    CAS  PubMed  Google Scholar 

  126. Biernaux C, Loos M, Sels A, Huez G, Stryckmans P . Detection of major bcr-abl gene expression at a very low level in blood cells of some healthy individuals. Blood 1995; 86: 3118–3122.

    CAS  PubMed  Google Scholar 

  127. Passamonti F, Rumi E, Pietra D, Lazzarino M, Cazzola M . JAK2 (V617F) mutation in healthy individuals. Br J Haematol 2007; 136: 678–679.

    PubMed  Google Scholar 

  128. McClure R, Mai M, Lasho T . Validation of two clinically useful assays for evaluation of JAK2 V617F mutation in chronic myeloproliferative disorders. Leukemia 2006; 20: 168–171.

    CAS  PubMed  Google Scholar 

  129. Bellanne-Chantelot C, Jego P, Lionne-Huyghe P, Tulliez M, Najman A . The JAK2(V617F) mutation may be present several years before the occurrence of overt myeloproliferative disorders. Leukemia 2007; 22: 450–451.

    PubMed  Google Scholar 

  130. Wang YL, Lee JW, Kui JS, Chadburn A, Cross NC, Knowles DM et al. Evaluation of JAK2 in B and T cell neoplasms: identification of JAK2(V617F) mutation of undetermined significance (JMUS) in the bone marrow of three individuals. Acta Haematol 2007; 118: 209–214.

    CAS  PubMed  Google Scholar 

  131. Larsen TS, Christensen JH, Hasselbalch HC, Pallisgaard N . The JAK2 V617F mutation involves B- and T-lymphocyte lineages in a subgroup of patients with Philadelphia-chromosome negative chronic myeloproliferative disorders. Br J Haematol 2007; 136: 745–751.

    CAS  PubMed  Google Scholar 

  132. Lasho TL, Mesa R, Gilliland DG, Tefferi A . Mutation studies in CD3+, CD19+ and CD34+ cell fractions in myeloproliferative disorders with homozygous JAK2(V617F) in granulocytes. Br J Haematol 2005; 130: 797–799.

    CAS  PubMed  Google Scholar 

  133. Delhommeau F, Dupont S, Tonetti C, Masse A, Godin I, Le Couedic JP et al. Evidence that the JAK2 G1849T (V617F) mutation occurs in a lympho-myeloid progenitor in polycythemia vera and idiopathic myelofibrosis. Blood 2006; 109: 71–77.

    PubMed  Google Scholar 

  134. Ishii T, Bruno E, Hoffman R, Xu M . Involvement of various hematopoietic-cell lineages by the JAK2V617F mutation in polycythemia vera. Blood 2006; 108: 3128–3134.

    CAS  PubMed  Google Scholar 

  135. Adamson JW, Fialkow PJ, Murphy S, Prchal JF, Steinmann L . Polycythemia vera: stem-cell and probable clonal origin of the disease. N Engl J Med 1976; 295: 913–916.

    CAS  PubMed  Google Scholar 

  136. Fujinaka Y, Takane K, Yamashita H, Vasavada RC . Lactogens promote beta cell survival through JAK2/STAT5 activation and BCL-XL upregulation. J Biol Chem 2007; 282: 30707–30717.

    CAS  PubMed  Google Scholar 

  137. Walz C, Crowley BJ, Hudon HE, Gramlich JL, Neuberg DS, Podar K et al. Activated Jak2 with the V617F point mutation promotes G1/S phase transition. J Biol Chem 2006; 281: 18177–18183.

    CAS  PubMed  Google Scholar 

  138. Sattler M, Verma S, Shrikhande G, Byrne CH, Pride YB, Winkler T et al. The BCR/ABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells. J Biol Chem 2000; 275: 24273–24278.

    CAS  PubMed  Google Scholar 

  139. Nowicki MO, Falinski R, Koptyra M, Slupianek A, Stoklosa T, Gloc E et al. BCR/ABL oncogenic kinase promotes unfaithful repair of the reactive oxygen species-dependent DNA double-strand breaks. Blood 2004; 104: 3746–3753.

    CAS  PubMed  Google Scholar 

  140. Sasaki A, Yasukawa H, Shouda T, Kitamura T, Dikic I, Yoshimura A . CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2. J Biol Chem 2000; 275: 29338–29347.

    CAS  PubMed  Google Scholar 

  141. Hookham MB, Elliott J, Suessmuth Y, Staerk J, Ward AC, Vainchenker W et al. The myeloproliferative disorder-associated JAK2 V617F mutant escapes negative regulation by suppressor of cytokine signaling 3. Blood 2007; 109: 4924–4929.

    CAS  PubMed  Google Scholar 

  142. Theocharides A, Boissinot M, Girodon F, Garand R, Teo SS, Lippert E et al. Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation. Blood 2007; 110: 375–379.

    CAS  PubMed  Google Scholar 

  143. Campbell PJ, Baxter EJ, Beer PA, Scott LM, Bench AJ, Huntly BJ et al. Mutation of JAK2 in the myeloproliferative disorders: timing, clonality studies, cytogenetic associations, and role in leukemic transformation. Blood 2006; 108: 3548–3555.

    CAS  PubMed  Google Scholar 

  144. Lacout C, Pisani DF, Tulliez M, Moreau GF, Vainchenker W, Villeval JL . JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis. Blood 2006; 108: 1652–1660.

    CAS  PubMed  Google Scholar 

  145. Scott LM, Scott MA, Campbell PJ, Green AR . Progenitors homozygous for the V617F mutation occur in most patients with polycythemia vera, but not essential thrombocythemia. Blood 2006; 108: 2435–2437.

    CAS  PubMed  Google Scholar 

  146. Tiedt R, Hao-Shen H, Sobas MA, Looser R, Dirnhofer S, Schwaller J et al. Ratio of mutant JAK2-V617F to wild type JAK2 determines the MPD phenotypes in transgenic mice. Blood 2008; 111: 3931–3940.

    CAS  PubMed  Google Scholar 

  147. Shide K, Shimoda HK, Kumano T, Karube K, Kameda T, Takenaka K et al. Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F. Leukemia 2007; 22: 87–95.

    PubMed  Google Scholar 

  148. Capello D, Deambrogi C, Rossi D, Lischetti T, Piranda D, Cerri M et al. Epigenetic inactivation of suppressors of cytokine signalling in Philadelphia-negative chronic myeloproliferative disorders. Br J Haematol 2008; 141: 504–511.

    CAS  PubMed  Google Scholar 

  149. Jost E, do ON, Dahl E, Maintz CE, Jousten P, Habets L et al. Epigenetic alterations complement mutation of JAK2 tyrosine kinase in patients with BCR/ABL-negative myeloproliferative disorders. Leukemia 2007; 21: 505–510.

    CAS  PubMed  Google Scholar 

  150. Kralovics R, Teo SS, Li S, Theocharides A, Buser AS, Tichelli A et al. Acquisition of the V617F mutation of JAK2 is a late genetic event in a subset of patients with myeloproliferative disorders. Blood 2006; 108: 1377–1380.

    CAS  PubMed  Google Scholar 

  151. Gale RE, Allen AJ, Nash MJ, Linch DC . Long-term serial analysis of X-chromosome inactivation patterns and JAK2 V617F mutant levels in patients with essential thrombocythemia show that minor mutant-positive clones can remain stable for many years. Blood 2007; 109: 1241–1243.

    CAS  PubMed  Google Scholar 

  152. Nussenzveig RH, Swierczek SI, Jelinek J, Gaikwad A, Liu E, Verstovsek S et al. Polycythemia vera is not initiated by JAK2(V617F) mutation. Exp Hematol 2007; 35: 32–38.

    CAS  PubMed  Google Scholar 

  153. Rumi E, Passamonti F, Pietra D, Della Porta MG, Arcaini L, Boggi S et al. JAK2 (V617F) as an acquired somatic mutation and a secondary genetic event associated with disease progression in familial myeloproliferative disorders. Cancer 2006; 107: 2206–2211.

    CAS  PubMed  Google Scholar 

  154. Lippert E, Boissinot M, Kralovics R, Girodon F, Dobo I, Praloran V et al. The JAK2-V617F mutation is frequently present at diagnosis in patients with essential thrombocythemia and polycythemia vera. Blood 2006; 108: 1865–1867.

    CAS  PubMed  Google Scholar 

  155. Fialkow PJ, Martin PJ, Najfeld V, Penfold GK, Jacobson RJ, Hansen JA . Evidence for a multistep pathogenesis of chronic myelogenous leukemia. Blood 1981; 58: 158–163.

    CAS  PubMed  Google Scholar 

  156. Apperley JF, Gardembas M, Melo JV, Russell-Jones R, Bain BJ, Baxter J 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 2002; 347: 481–487.

    CAS  PubMed  Google Scholar 

  157. Baccarani M, Cilloni D, Rondoni M, Ottaviani F, Messa F, Merante S et al. Imatinib mesylate induces complete and durable responses in all patients with the FIP1L1-PDGFRa positive hypereosinophilic syndrome. Results of a multicenter study. Haematologica 2007; 92: 1173–1179.

    CAS  PubMed  Google Scholar 

  158. Kantarjian HM, Talpaz M, O'Brien S, Jones D, Giles F, Garcia-Manero G et al. Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia. Blood 2006; 108: 1835–1840.

    CAS  PubMed  Google Scholar 

  159. Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355: 2408–2417.

    CAS  PubMed  Google Scholar 

  160. Hughes T . ABL kinase inhibitor therapy for CML: baseline assessments and response monitoring. Hematology Am Soc Hematol Educ Program 2006, 211–218.

    Google Scholar 

  161. Hughes T, Branford S . Molecular monitoring of BCR-ABL as a guide to clinical management in chronic myeloid leukaemia. Blood Rev 2006; 20: 29–41.

    CAS  PubMed  Google Scholar 

  162. Rousselot P, Huguet F, Rea D, Legros L, Cayuela JM, Maarek O et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 2007; 109: 58–60.

    CAS  PubMed  Google Scholar 

  163. Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002; 99: 319–325.

    CAS  PubMed  Google Scholar 

  164. Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006; 108: 28–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006; 108: 1809–1820.

    CAS  PubMed  Google Scholar 

  166. Picard S, Titier K, Etienne G, Teilhet E, Ducint D, Bernard MA et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2007; 109: 3496–3499.

    CAS  PubMed  Google Scholar 

  167. Pocaly M, Lagarde V, Etienne G, Ribeil JA, Claverol S, Bonneu M et al. Overexpression of the heat-shock protein 70 is associated to imatinib resistance in chronic myeloid leukemia. Leukemia 2007; 21: 93–101.

    CAS  PubMed  Google Scholar 

  168. White DL, Saunders VA, Dang P, Engler J, Venables A, Zrim S et al. Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood 2007; 110: 4064–4072.

    CAS  PubMed  Google Scholar 

  169. Larson RA, Druker BJ, Guilhot FA, O'Brien SG, Riviere GJ, Krahnke T et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 2008; 111: 4022–4028.

    CAS  PubMed  Google Scholar 

  170. Wang Y, Cai D, Brendel C, Barett C, Erben P, Manley PW et al. Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation. Blood 2007; 109: 2147–2155.

    CAS  PubMed  Google Scholar 

  171. le Coutre P, Ottmann OG, Giles F, Kim DW, Cortes J, Gattermann N et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated phase chronic myelogenous leukemia. Blood 2007; 111: 1834–1839.

    PubMed  Google Scholar 

  172. Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 2007; 110: 3540–3546.

    CAS  PubMed  Google Scholar 

  173. Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006; 354: 2542–2551.

    PubMed  Google Scholar 

  174. Rix U, Hantschel O, Durnberger G, Remsing Rix LL, Planyavsky M, Fernbach NV et al. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood 2007; 110: 4055–4063.

    CAS  PubMed  Google Scholar 

  175. Hantschel O, Rix U, Schmidt U, Burckstummer T, Kneidinger M, Schutze G et al. The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib. Proc Natl Acad Sci USA 2007; 104: 13283–13288.

    CAS  PubMed  PubMed Central  Google Scholar 

  176. von Bubnoff N, Manley PW, Mestan J, Sanger J, Peschel C, Duyster J . Bcr-Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107). Blood 2006; 108: 1328–1333.

    CAS  PubMed  Google Scholar 

  177. Soverini S, Martinelli G, Colarossi S, Gnani A, Rondoni M, Castagnetti F et al. Second-line treatment with dasatinib in patients resistant to imatinib can select novel inhibitor-specific BCR-ABL mutants in Ph+ ALL. Lancet Oncol 2007; 8: 273–274.

    PubMed  Google Scholar 

  178. Soverini S, Colarossi S, Gnani A, Castagnetti F, Rosti G, Bosi C et al. Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain. Haematologica 2007; 92: 401–404.

    CAS  PubMed  Google Scholar 

  179. Guilhot F, Apperley J, Kim DW, Bullorsky EO, Baccarani M, Roboz GJ et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 2007; 109: 4143–4150.

    CAS  PubMed  Google Scholar 

  180. Shah NP, Kim DW, Kantarjian HM, Rousselot P, Dorlhiac-Llacer PE, Milone JE et al. Dasatinib 50 or 70 mg BID compared to 100 or 140 mg QD in patients with CML in chronic phase (CP) who are resistant or intolerant to imatinib: One-year results of CA180034. J Clin Oncol 2007; 25 (18S (June 20 Supplement): 7004.

    Google Scholar 

  181. Puttini M, Coluccia AM, Boschelli F, Cleris L, Marchesi E, Donella-Deana A et al. In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl+ neoplastic cells. Cancer Res 2006; 66: 11314–11322.

    CAS  PubMed  Google Scholar 

  182. Konig H, Holyoake TL, Bhatia R . Effective and selective inhibition of chronic myeloid leukemia primitive hematopoietic progenitors by the dual Src/Abl kinase inhibitor SKI-606. Blood 2008; 111: 2329–2338.

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Morinaga K, Yamauchi T, Kimura S, Maekawa T, Ueda T . Overcoming imatinib resistance using Src inhibitor CGP76030, Abl inhibitor nilotinib and Abl/Lyn inhibitor INNO-406 in newly established K562 variants with BCR-ABL gene amplification. Int J Cancer 2008; 122: 2621–2627.

    CAS  PubMed  Google Scholar 

  184. Deguchi Y, Kimura S, Ashihara E, Niwa T, Hodohara K, Fujiyama Y et al. Comparison of imatinib, dasatinib, nilotinib and INNO-406 in imatinib-resistant cell lines. Leuk Res 2008; 32: 980–983.

    CAS  PubMed  Google Scholar 

  185. Giles FJ, Cortes J, Jones D, Bergstrom D, Kantarjian H, Freedman SJ . MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood 2007; 109: 500–502.

    CAS  PubMed  Google Scholar 

  186. Shah NP, Skaggs BJ, Branford S, Hughes TP, Nicoll JM, Paquette RL et al. Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency. J Clin Invest 2007; 117: 2562–2569.

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Thomas DA . Philadelphia chromosome positive acute lymphocytic leukemia: a new era of challenges. Hematology Am Soc Hematol Educ Program 2007; 2007: 435–443.

    Google Scholar 

  188. Verstovsek S, Kantarjian H, Pardanani A, Thomas D, Cortes J, Mesa R et al. NCB018424, an oral, selective JAK2 inhibitor, shows significant clinical activity in a Phase I/II Study in patients with primary myelofibrosis (PMF) and post polycythemia vera/essential thrombocythemia myelofibrosis (Post-PV/ET MF). Blood 2007; 110: 162.

    Google Scholar 

  189. Verstovsek S, Pardanani A, Shah NP, Sokol L, Wadleigh M, Gilliland DG et al. A Phase I Study of XL019, a selective JAK2 inhibitor, in patients with primary myelofibrosis and post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood 2007; 110: 162.

    Google Scholar 

  190. Pardanani A . JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials. Leukemia 2007; 22: 23–30.

    PubMed  Google Scholar 

  191. Nosaka T, van Deursen JM, Tripp RA, Thierfelder WE, Witthuhn BA, McMickle AP et al. Defective lymphoid development in mice lacking Jak3. Science 1995; 270: 800–802.

    CAS  PubMed  Google Scholar 

  192. Guerini V, Barbui V, Spinelli O, Salvi A, Dellacasa C, Carobbio A et al. The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2(V617F). Leukemia 2008; 22: 740–747.

    CAS  PubMed  Google Scholar 

  193. Pardanani A, Hood J, Lasho T, Levine RL, Martin MB, Noronha G et al. TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. Leukemia 2007; 21: 1658–1668.

    CAS  PubMed  Google Scholar 

  194. Hexner EO, Serdikoff C, Jan M, Swider CR, Robinson C, Yang S et al. Lestaurtinib (CEP701)is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood 2008; (in press).

  195. Grandage VL, Everington T, Linch DC, Khwaja A . Go6976 is a potent inhibitor of the JAK 2 and FLT3 tyrosine kinases with significant activity in primary acute myeloid leukaemia cells. Br J Haematol 2006; 135: 303–316.

    CAS  PubMed  Google Scholar 

  196. Zaleskas VM, Chang WW, Evangelista P, Lazarides K, Chopra R, Zinda M et al. A selective and potent oral inhibitor of the JAK2 tyrosine kinase reverses polycythemia and leukocytosis induced by JAK2 V617F in a mouse model. Blood 2007; 110: 171a.

    Google Scholar 

  197. Wernig G, Kharas MG, Okabe R, Moore SA, Leeman DS, Cullen DE et al. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Blood 2007; 110: 171a.

    Google Scholar 

  198. Neubauer H, Cumano A, Muller M, Wu H, Huffstadt U, Pfeffer K . Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 1998; 93: 397–409.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

CW is supported by a postdoc fellowship of the DFG (German Research Foundation). RAV is supported by NIN Grant HL089747 and an SCOR grant from the Leukemia and Lymphoma Society. AR is supported by the ‘Deutsche José Carreras Leukämie-Stiftung e.V.’ (Grant no. DJCLS R06/02), Germany, the Competence Network ‘Acute and chronic leukemias’, sponsored by the German Bundesministerium für Bildung und Forschung (Projektträger Gesundheitsforschung; DLR e.V.-01GI9980/6), the ‘European LeukemiaNet’ within the 6th European Community Framework Programme for Research and Technological Development.

Author information

Authors and Affiliations

  1. Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA

    C Walz & R A Van Etten

  2. Salisbury and Human Genetics Division, Wessex Regional Genetics Laboratory, University of Southampton, Southampton, UK

    N C P Cross

  3. III. Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany

    A Reiter

Authors
  1. C Walz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N C P Cross
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R A Van Etten
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Reiter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Reiter.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Walz, C., Cross, N., Van Etten, R. et al. Comparison of mutated ABL1 and JAK2 as oncogenes and drug targets in myeloproliferative disorders. Leukemia 22, 1320–1334 (2008). https://doi.org/10.1038/leu.2008.133

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2008.133

Keywords

This article is cited by

Search

Advanced search

Quick links