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JAK2 and MPL mutations in myeloproliferative neoplasms: discovery and science

Abstract

Although it has long been known that the myeloproliferative neoplasms (MPN) polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are clonal hematopoietic stem-cell disorders, for many years the genetic basis for these disorders was elusive. A new era in MPN biology began in 2005 with the discovery of a somatic point mutation in JAK2 tyrosine kinase (JAK2V617F), which was identified in a significant proportion of patients with PV, ET and PMF. Based on the hypothesis that JAK-STAT signaling is central to the pathogenesis of JAK2V617F-negative MPN, genomic studies have identified JAK2 exon 12 mutations in JAK2V617F-negative PV and activating mutations in MPL in patients with JAK2V617F-negative ET and PMF. In this review, we will discuss the role of these mutant alleles in the pathogenesis of PV, ET and PMF, the potential therapeutic implications of these discoveries, and the implications of these discoveries for genomic studies of hematopoietic malignancies.

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References

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

    CAS  PubMed  Google Scholar 

  2. Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 2007; 110: 1092–1097.

    Article  CAS  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003; 348: 1201–1214.

    Article  CAS  PubMed  Google Scholar 

  5. Golub T, Barker G, Lovett M, Gilliland D . Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 1994; 77: 307–316.

    Article  CAS  PubMed  Google Scholar 

  6. Fialkow P, Gartler SM, Yoshida A . Clonal origin of chronic myelocytic leukemia in man. Proc Natl Acad Sci USA 1967; 58: 1468–1471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. Tsukamoto N, Morita K, Maehara T, Okamoto K, Sakai H, Karasawa M et al. Clonality in chronic myeloproliferative disorders defined by X-chromosome linked probes: demonstration of heterogeneity in lineage involvement. British Journal of Haematology 1994; 86: 253–258.

    Article  CAS  PubMed  Google Scholar 

  9. El Kassar N, Hetet G, Li Y, Briere J, Grandchamp B . Clonal analysis of haemopoietic cells in essential thrombocythaemia. Br J Haem 1995; 90: 131–137.

    Article  CAS  Google Scholar 

  10. Prchal JF, Axelrad AA . Letter: Bone-marrow responses in polycythemia vera. N Engl J Med 1974; 290: 1382.

    CAS  PubMed  Google Scholar 

  11. Lutton JD, Levere RD . Endogenous erythroid colony formation by peripheral blood mononuclear cells from patients with myelofibrosis and polycythemia vera. Acta Haematol 1979; 62: 94–99.

    Article  CAS  PubMed  Google Scholar 

  12. Silva M, Richard C, Benito A, Sanz C, Olalla I, Fernandez-Luna JL . Expression of Bcl-x in erythroid precursors from patients with polycythemia vera. N Engl J Med 1998; 338: 564–571.

    Article  CAS  PubMed  Google Scholar 

  13. Moliterno AR, Hankins WD, Spivak JL . Impaired expression of the thrombopoietin receptor by platelets from patients with polycythemia vera. N Engl J Med 1998; 338: 572–580.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Article  CAS  PubMed  Google Scholar 

  15. 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.

    Article  CAS  PubMed  Google Scholar 

  16. 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 

  17. 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 

  18. Ugo V, Marzac C, Teyssandier I, Larbret F, Lecluse Y, Debili N et al. Multiple signaling pathways are involved in erythropoietin-independent differentiation of erythroid progenitors in polycythemia vera. Exp Hematol 2004; 32: 179–187.

    Article  CAS  PubMed  Google Scholar 

  19. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G et al. Patterns of somatic mutation in human cancer genomes. Nature 2007; 446: 153–158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Frohling S, Scholl C, Levine RL, Loriaux M, Boggon TJ, Bernard OA et al. Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles. Cancer Cell 2007; 12: 501–513.

    Article  CAS  PubMed  Google Scholar 

  21. Kralovics R, Guan Y, Prchal JT . Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera. Exp Hematol 2002; 30: 229–236.

    Article  CAS  PubMed  Google Scholar 

  22. Frohling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 2002; 100: 4372–4380.

    Article  CAS  PubMed  Google Scholar 

  23. Gondek LP, Dunbar AJ, Szpurka H, McDevitt MA, Maciejewski JP . SNP array karyotyping allows for the detection of uniparental disomy and cryptic chromosomal abnormalities in MDS/MPD-U and MPD. PLoS ONE 2007; 2: e1225.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Raghavan M, Smith LL, Lillington DM, Chaplin T, Kakkas I, Molloy G et al. Segmental uniparental disomy is a commonly acquired genetic event in relapsed acute myeloid leukemia. Blood 2008; 112: 814–821.

    Article  CAS  PubMed  Google Scholar 

  25. Bardelli A, Parsons DW, Silliman N, Ptak J, Szabo S, Saha S et al. Mutational analysis of the tyrosine kinome in colorectal cancers. Science 2003; 300: 949.

    Article  CAS  PubMed  Google Scholar 

  26. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304: 1497–1500.

    Article  CAS  PubMed  Google Scholar 

  27. Loriaux MM, Levine RL, Tyner JW, Frohling S, Scholl C, Stoffregen EP et al. High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia. Blood 2008; 111: 4788–4796.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dusa A, Staerk J, Elliott J, Pecquet C, Poirel HA, Johnston JA et al. Substitution of pseudokinase domain residue Val-617 by large non-polar amino acids causes activation of JAK2. J Biol Chem 2008; 283: 12941–12948.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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.

    Article  CAS  PubMed  Google Scholar 

  31. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  33. 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 

  34. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Bumm TG, Elsea C, Corbin AS, Loriaux M, Sherbenou D, Wood L et al. Characterization of murine JAK2V617F-positive myeloproliferative disease. Cancer Res 2006; 66: 11156–11165.

    Article  CAS  PubMed  Google Scholar 

  36. 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. Cancer Cell 2008; 13: 311–320.

    Article  CAS  PubMed  Google Scholar 

  37. Levine RL, Belisle C, Wadleigh M, Zahrieh D, Lee S, Chagnon P et al. X-inactivation-based clonality analysis and quantitative JAK2V617F assessment reveal a strong association between clonality and JAK2V617F in PV but not ET/MMM, and identifies a subset of JAK2V617F-negative ET and MMM patients with clonal hematopoiesis. Blood 2006; 107: 4139–4141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kiladjian JJ, Cervantes F, Leebeek FW, Marzac C, Cassinat B, Chevret S et al. The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases. Blood 2008; 111: 4922–4929.

    Article  CAS  PubMed  Google Scholar 

  39. 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.

    Article  CAS  PubMed  Google Scholar 

  40. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lasho TL, Tefferi A, Hood JD, Verstovsek S, Gilliland DG, Pardanani A . TG101348, a JAK2-selective antagonist, inhibits primary hematopoietic cells derived from myeloproliferative disorder patients with JAK2V617F, MPLW515K or JAK2 exon 12 mutations as well as mutation negative patients. Leukemia 2008: published online.

  42. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  43. 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 

  44. Chaligne R, Tonetti C, Besancenot R, Roy L, Marty C, Mossuz P et al. New mutations of MPL in primitive myelofibrosis: only the MPL W515 mutations promote a G(1)/S-phase transition. Leukemia 2008: published online.

  45. Beer PA, Campbell PJ, Scott LM, Bench AJ, Erber WN, Bareford D et al. MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood 2008; 112: 141–149.

    Article  CAS  PubMed  Google Scholar 

  46. Ding J, Komatsu H, Wakita A, Kato-Uranishi M, Ito M, Satoh A et al. Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin. Blood 2004; 103: 4198–4200.

    Article  CAS  PubMed  Google Scholar 

  47. Vannucchi AM, Antonioli E, Guglielmelli P, Pancrazzi A, Guerini V, Barosi G et al. Characteristics and clinical correlates of MPL 515W>L/K mutation in essential thrombocythemia. Blood 2008; 112: 844–847.

    Article  CAS  PubMed  Google Scholar 

  48. Guglielmelli P, Pancrazzi A, Bergamaschi G, Rosti V, Villani L, Antonioli E et al. Anaemia characterises patients with myelofibrosis harbouring Mpl mutation. Br J Haematol 2007; 137: 244–247.

    Article  CAS  PubMed  Google Scholar 

  49. 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.

    Article  CAS  PubMed  Google Scholar 

  50. 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.

    Article  CAS  PubMed  Google Scholar 

  51. Xing S, Wanting TH, Zhao W, Ma J, Wang S, Xu X et al. Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice. Blood 2008; 111: 5109–5117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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 2008; 22: 87–95.

    Article  CAS  PubMed  Google Scholar 

  53. Pardanani A, Fridley BL, Lasho TL, Gilliland DG, Tefferi A . Host genetic variation contributes to phenotypic diversity in myeloproliferative disorders. Blood 2008; 111: 2785–2789.

    Article  CAS  PubMed  Google Scholar 

  54. Kralovics R, Stockton DW, Prchal JT . Clonal hematopoiesis in familial polycythemia vera suggests the involvement of multiple mutational events in the early pathogenesis of the disease. Blood 2003; 102: 3793–3796.

    Article  CAS  PubMed  Google Scholar 

  55. Cario H, Goerttler PS, Steimle C, Levine RL, Pahl HL . The JAK2V617F mutation is acquired secondary to the predisposing alteration in familial polycythaemia vera. Br J Haematol 2005; 130: 800–801.

    Article  CAS  PubMed  Google Scholar 

  56. Bellanne-Chantelot C, Chaumarel I, Labopin M, Bellanger F, Barbu V, De Toma C et al. Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders. Blood 2006; 108: 346–352.

    Article  CAS  PubMed  Google Scholar 

  57. Landgren O, Goldin LR, Kristinsson SY, Helgadottir EA, Samuelsson J, Bjorkholm M . Increased risks of polycythemia vera, essential thrombocythemia, and myelofibrosis among 24577 first-degree relatives of 11039 patients with myeloproliferative neoplasms in Sweden. Blood 2008: published online.

  58. Asimakopoulos FA, White NJ, Nacheva E, Green AR . Molecular analysis of chromosome 20q deletions associated with myeloproliferative disorders and myelodysplastic syndromes. Blood 1994; 84: 3086–3094.

    CAS  PubMed  Google Scholar 

  59. 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.

    Article  CAS  PubMed  Google Scholar 

  60. 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.

    Article  CAS  PubMed  Google Scholar 

  61. 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.

    Article  CAS  PubMed  Google Scholar 

  62. Lu X, Levine R, Tong W, Wernig G, Pikman Y, Zarnegar S et al. Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation. Proc Natl Acad Sci USA 2005; 102: 18962–18967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Garcon L, Rivat C, James C, Lacout C, Camara-Clayette V, Ugo V et al. Constitutive activation of STAT5 and Bcl-xL overexpression can induce endogenous erythroid colony formation in human primary cells. Blood 2006; 108: 1551–1554.

    Article  CAS  PubMed  Google Scholar 

  64. 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.

    Article  CAS  PubMed  Google Scholar 

  65. Verstovek S, Kantarjian H, Pardanani A, Thomas D, Cortes J, Mesa R et al. A phase I/II study of ICNB018424, an oral, selective JAK inhibitor, in patients with primary myelofibrosis and postPV/ET myelofibrosis. American Socierty of Clincial Oncology Annual Meeting 2008, Abstract 7004.

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Acknowledgements

We acknowledge the patients, physicians, and investigators who have contributed to our understanding of these disorders. The Levine Laboratory is supported by the US National Institutes of Health, the Howard Hughes Medical Institute Early Career Award Program, the American Society of Hematology, and the Doris Duke Charitable Foundation Clinical Scientist Development Award program. RLL is an American Society of Hematology Basic Research Fellow and is the Geoffrey Beene Junior Chair at Memorial Sloan Kettering Cancer Center.

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Kilpivaara, O., Levine, R. JAK2 and MPL mutations in myeloproliferative neoplasms: discovery and science. Leukemia 22, 1813–1817 (2008). https://doi.org/10.1038/leu.2008.229

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Keywords

  • myeloproliferative neoplasms
  • JAK2
  • MPL

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