How does JAK2V617F contribute to the pathogenesis of myeloproliferative neoplasms?

Hematology (United States)

Volumn 2014, Issue 1, 2014, Pages 268-276

  Chen, Edwin ^a   Mullally, Ann ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

JAK2 PROTEIN, HUMAN; JANUS KINASE 2;

ANTAGONISTS AND INHIBITORS; CYTOLOGY; ENZYMOLOGY; GENETICS; HEMATOPOIETIC STEM CELL; HUMAN; MOLECULARLY TARGETED THERAPY; MUTATION; MYELOPROLIFERATIVE DISORDERS; PHENOTYPE;

HEMATOPOIETIC STEM CELLS; HUMANS; JANUS KINASE 2; MOLECULAR TARGETED THERAPY; MUTATION; MYELOPROLIFERATIVE DISORDERS; PHENOTYPE;

EID: 84937541578     PISSN: 15204391     EISSN: 15204383     Source Type: Journal    
DOI: 10.1182/asheducation-2014.1.268     Document Type: Article

References (97)

1. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365(9464):1054-1061.
2. James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144-1148.
3. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352(17): 1779-1790.
4. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7(4):387-397.
5. Dameshek W. Some speculations on the myeloproliferative syndromes. Blood. 1951;6(4):372-375.
6. Prchal JF, Axelrad AA. Letter: Bone-marrow responses in polycythemia vera. N Engl J Med. 1974;290(24):1382.
7. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356(5):459-468.
8. Ma W, Kantarjian H, Zhang X, et al. Mutation profile of JAK2 transcripts in patients with chronic myeloproliferative neoplasias. J Mol Diagn. 2009;11(1):49-53.
9. Bandaranayake RM, Ungureanu D, Shan Y, Shaw DE, Silvennoinen O, Hubbard SR. Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F. Nat Struct Mol Biol. 2012;19(8):754-759.
10. Toms AV, Deshpande A, McNally R, et al. Structure of a pseudokinasedomain switch that controls oncogenic activation of Jak kinases. Nat Struct Mol Biol. 2013;20(10):1221-1223.
11. Shan Y, Gnanasambandan K, Ungureanu D, et al. Molecular basis for pseudokinase-dependent autoinhibition of JAK2 tyrosine kinase. Nat Struct Mol Biol. 2014;21(7):579-584.
12. Ungureanu D, Wu J, Pekkala T, et al. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling. Nat Struct Mol Biol. 2011;18(9):971-976.
13. Brooks AJ, Dai W, O'Mara ML, et al. Mechanism of activation of protein kinase JAK2 by the growth hormone receptor. Science. 2014; 344(6185):1249783.
14. Lu X, Levine R, Tong W, et al. Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation. Proc Natl Acad Sci U S A. 2005;102(52):18962-18967.
15. Lu X, Huang LJ, Lodish HF. Dimerization by a cytokine receptor is necessary for constitutive activation of JAK2V617F. J Biol Chem. 2008;283(9):5258-5266.
16. Pradhan A, Lambert QT, Reuther GW. Transformation of hematopoietic cells and activation of JAK2-V617F by IL-27R, a component of a heterodimeric type I cytokine receptor. Proc Natl Acad Sci U S A. 2007;104(47):18502-18507.
17. Pradhan A, Lambert QT, Griner LN, Reuther GW. Activation of JAK2-V617F by components of heterodimeric cytokine receptors. J Biol Chem. 2010;285(22):16651-16663.
18. Wernig G, Gonneville JR, Crowley BJ, et al. The Jak2V617F oncogene associated with myeloproliferative diseases requires a functional FERM domain for transformation and for expression of the Myc and Pim proto-oncogenes. Blood. 2008;111(7):3751-3759.
19. da Costa Reis Monte-Mor B, Plo I, da Cunha AF, et al. Constitutive JunB expression, associated with the JAK2 V617F mutation, stimulates proliferation of the erythroid lineage. Leukemia. 2009;23(1):144-152.
20. Funakoshi-Tago M, Sumi K, Kasahara T, Tago K. Critical roles of Myc-ODC axis in the cellular transformation induced by myeloproliferative neoplasm-associated JAK2 V617F mutant. PLoS One. 2013;8(1): e52844.
21. Walz C, Crowley BJ, Hudon HE, et al. Activated Jak2 with the V617F point mutation promotes G1/S phase transition. J Biol Chem. 2006; 281(26):18177-18183.
22. Gautier EF, Picard M, Laurent C, et al. The cell cycle regulator CDC25A is a target for JAK2V617F oncogene. Blood. 2012;119(5): 1190-1199.
23. Wood AD, Chen E, Donaldson IJ, et al. ID1 promotes expansion and survival of primary erythroid cells and is a target of JAK2V617FSTAT5 signaling. Blood. 2009;114(9):1820-1830.
24. Irino T, Uemura M, Yamane H, et al. JAK2 V617F-dependent upregulation of PU.1 expression in the peripheral blood of myeloproliferative neoplasm patients. PLoS One. 2011;6(7):e22148.
25. Garcon L, Rivat C, James C, et al. Constitutive activation of STAT5 and Bcl-xL overexpression can induce endogenous erythroid colony formation in human primary cells. Blood. 2006;108(5):1551-1554.
26. Rubert J, Qian Z, Andraos R, Guthy DA, Radimerski T. Bim and Mcl-1 exert key roles in regulating JAK2V617F cell survival. BMC Cancer. 2011;11:24.
27. Plo I, Nakatake M, Malivert L, et al. JAK2 stimulates homologous recombination and genetic instability: potential implication in the heterogeneity of myeloproliferative disorders. Blood. 2008;112(4):1402-1412.
28. Walz C, Ahmed W, Lazarides K, et al. Essential role for Stat5a/b in myeloproliferative neoplasms induced by BCR-ABL1 and JAK2(V617F) in mice. Blood. 2012;119(15):3550-3560.
29. Yan D, Hutchison RE, Mohi G. Critical requirement for Stat5 in a mouse model of polycythemia vera. Blood. 2012;119(15):3539-3549.
30. Mesa RA, Tefferi A, Lasho TS, et al. Janus kinase 2 (V617F) mutation status, signal transducer and activator of transcription-3 phosphorylation and impaired neutrophil apoptosis in myelofibrosis with myeloid metaplasia. Leukemia. 2006;20(10):1800-1808.
31. Liu F, Zhao X, Perna F, et al. JAK2V617F-mediated phosphorylation of PRMT5 downregulates its methyltransferase activity and promotes myeloproliferation. Cancer Cell. 2011;19(2):283-294.
32. Nakatake M, Monte-Mor B, Debili N, et al. JAK2(V617F) negatively regulates p53 stabilization by enhancing MDM2 via La expression in myeloproliferative neoplasms. Oncogene. 2012;31(10):1323-1333.
33. Marty C, Lacout C, Droin N, et al. A role for reactive oxygen species in JAK2 V617F myeloproliferative neoplasm progression. Leukemia. 2013;27(11):2187-2195.
34. Hoermann G, Cerny-Reiterer S, Herrmann H, et al. Identification of oncostatin M as a JAK2 V617F-dependent amplifier of cytokine production and bone marrow remodeling in myeloproliferative neoplasms. FASEB J. 2012;26(2):894-906.
35. Rui L, Emre NC, Kruhlak MJ, et al. Cooperative epigenetic modulation by cancer amplicon genes. Cancer Cell. 2010;18(6):590-605.
36. Dawson MA, Bannister AJ, Gottgens B, et al. JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. Nature. 2009;461(7265):819-822.
37. 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(3):229-236.
38. Beer PA, Delhommeau F, LeCouedic JP, et al. Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm. Blood. 2010;115(14):2891-2900.
39. Tefferi A, Lasho TL, Schwager SM, et al. The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia vera. Cancer. 2006;106(3):631-635.
40. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Clinical profile of homozygous JAK2 617V+F mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007;110(3):840-846.
41. Tiedt R, Hao-Shen H, Sobas MA, et al. Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood. 2008;111(8):3931-3940.
42. Godfrey AL, Chen E, Pagano F, et al. JAK2V617F homozygosity arises commonly and recurrently in PV and ET, but PV is characterized by expansion of a dominant homozygous subclone. Blood. 2012;120(13): 2704-2707.
43. Chen E, Beer PA, Godfrey AL, et al. Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling. Cancer Cell. 2010;18(5):524-535.
44. Huang Z, Richmond TD, Muntean AG, Barber DL, Weiss MJ, Crispino JD. STAT1 promotes megakaryopoiesis downstream of GATA-1 in mice. J Clin Invest. 2007;117(12):3890-3899.
45. Duek A, Lundberg P, Shimizu T, et al. Loss of Stat1 decreases megakaryopoiesis and favors erythropoiesis in a JAK2-V617F driven mouse model of myeloproliferative neoplasms. Blood. 2014;123(25): 3943-3950.
46. Anand S, Stedham F, Gudgin E, et al. Increased basal intracellular signaling patterns do not correlate with JAK2 genotype in human myeloproliferative neoplasms. Blood. 2011;118(6):1610-1621.
47. Teofili L, Martini M, Cenci T, et al. Different STAT-3 and STAT-5 phosphorylation discriminates among Ph-negative chronic myeloproliferative diseases and is independent of the V617F JAK-2 mutation. Blood. 2007;110(1):354-359.
48. Pardanani A, Fridley BL, Lasho TL, Gilliland DG, Tefferi A. Host genetic variation contributes to phenotypic diversity in myeloproliferative disorders. Blood. 2008;111(5):2785-2789.
49. Stein BL, Williams DM, Wang NY, et al. Sex differences in the JAK2 V617F allele burden in chronic myeloproliferative disorders. Haematologica. 2010;95(7):1090-1097.
50. Godfrey AL, Chen E, Pagano F, Silber Y, Campbell PJ, Green AR. Clonal analyses reveal associations of JAK2V617F homozygosity with hematologic features, age and gender in polycythemia vera and essential thrombocythemia. Haematologica. 2013;98(5):718-721.
51. Jamieson CH, Gotlib J, Durocher JA, et al. The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation. Proc Natl Acad Sci U S A. 2006;103(16): 6224-6229.
52. Ishii T, Bruno E, Hoffman R, Xu M. Involvement of various hematopoietic-cell lineages by the JAK2V617F mutation in polycythemia vera. Blood. 2006;108(9):3128-3134.
53. Delhommeau F, Dupont S, Tonetti C, et al. Evidence that the JAK2 G1849T (V617F) mutation occurs in a lymphomyeloid progenitor in polycythemia vera and idiopathic myelofibrosis. Blood. 2007;109(1):71-77.
54. Anand S, Stedham F, Beer P, et al. Effects of the JAK2 mutation on the hematopoietic stem and progenitor compartment in human myeloproliferative neoplasms. Blood. 2011;118(1):177-181.
55. Stein BL, Williams DM, Rogers O, Isaacs MA, Spivak JL, Moliterno AR. Disease burden at the progenitor level is a feature of primary myelofibrosis: a multivariable analysis of 164 JAK2 V617F-positive myeloproliferative neoplasm patients. Exp Hematol. 2011;39(1):95-101.
56. Xu X, Zhang Q, Luo J, et al. JAK2(V617F): Prevalence in a large Chinese hospital population. Blood. 2007;109(1):339-342.
57. Nielsen C, Birgens HS, Nordestgaard BG, Kjaer L, Bojesen SE. The JAK2 V617F somatic mutation, mortality and cancer risk in the general population. Haematologica. 2011;96(3):450-453.
58. Dupont S, Masse A, James C, 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(3):1013-1021.
59. 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 mutantpositive clones can remain stable for many years. Blood. 2007;109(3): 1241-1243.
60. Cervantes F, Tassies D, Salgado C, Rovira M, Pereira A, Rozman C. Acute transformation in nonleukemic chronic myeloproliferative disorders: actuarial probability and main characteristics in a series of 218 patients. Acta Haematol. 1991;85(3):124-127.
61. Campbell PJ, Baxter EJ, Beer PA, et al. Mutation of JAK2 in the myeloproliferative disorders: timing, clonality studies, cytogenetic associations, and role in leukemic transformation. Blood. 2006;108(10): 3548-3555.
62. Theocharides A, Boissinot M, Girodon F, et al. Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation. Blood. 2007;110(1): 375-379.
63. Xu M, Bruno E, Chao J, et al. The constitutive mobilization of bone marrow-repopulating cells into the peripheral blood in idiopathic myelofibrosis. Blood. 2005;105(4):1699-1705.
64. Wang X, Prakash S, Lu M, et al. Spleens of myelofibrosis patients contain malignant hematopoietic stem cells. J Clin Invest. 2012;122(11): 3888-3899.
65. Ishii T, Zhao Y, Sozer S, et al. Behavior of CD34+ cells isolated from patients with polycythemia vera in NOD/SCID mice. Exp Hematol. 2007;35(11):1633-1640.
66. James C, Mazurier F, Dupont S, et al. The hematopoietic stem cell compartment of JAK2V617F-positive myeloproliferative disorders is a reflection of disease heterogeneity. Blood. 2008;112(6):2429-2438.
67. Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360(22):2289-2301.
68. Mullally A, Lane SW, Ball B, et al. Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells. Cancer Cell. 2010;17(6):584-596.
69. Mullally A, Poveromo L, Schneider RK, Al-Shahrour F, Lane SW, Ebert BL. Distinct roles for long-term hematopoietic stem cells and erythroid precursor cells in a murine model of Jak2V617F-mediated polycythemia vera. Blood. 2012;120(1):166-172.
70. Hasan S, Lacout C, Marty C, et al. JAK2V617F expression in mice amplifies early hematopoietic cells and gives them a competitive advantage that is hampered by IFNalpha. Blood. 2013;122(8):1464-1477.
71. Li J, Spensberger D, Ahn JS, et al. JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia. Blood. 2010;116(9):1528-1538.
72. Li J, Kent DG, Godfrey AL, et al. JAK2V617F homozygosity drives a phenotypic switch in myeloproliferative neoplasms, but is insufficient to sustain disease. Blood. 2014;123(20):3139-3151.
73. Kent DG, Li J, Tanna H, et al. Self-renewal of single mouse hematopoietic stem cells is reduced by JAK2V617F without compromising progenitor cell expansion. PLoS Biol. 2013;11(6):e1001576.
74. Kubovcakova L, Lundberg P, Grisouard J, et al. Differential effects of hydroxyurea and INC424 on mutant allele burden and myeloproliferative phenotype in a JAK2-V617F polycythemia vera mouse model. Blood. 2013;121(7):1188-1199.
75. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798.
76. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebocontrolled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012; 366(9):799-807.
77. Verstovsek S, Mesa RA, Gotlib J, et al. Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: results of a median 2-year follow-up of COMFORT-I. Haematologica. 2013;98(12):1865-1871.
78. Cervantes F, Vannucchi AM, Kiladjian JJ, et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood. 2013;122(25):4047-4053.
79. Pardanani A, Laborde RR, Lasho TL, et al. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia. 2013;27(6):1322-1327.
80. Vainchenker W, Favale F. Myelofibrosis, JAK2 inhibitors and erythropoiesis. Leukemia. 2013;27(6):1219-1223.
81. Guglielmelli P, Biamonte F, Rotunno G, et al. Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study. Blood. 2014;123(14):2157-2160.
82. Kvasnicka HM, Thiele J, Bueso-Ramos BR, et al. Exploratory analysis of the effect of ruxolitinib on bone marrow morphology in patients with myelofibrosis [abstract]. J Clin Oncol. 2013;31(suppl):7030.
83. Park SO, Wamsley HL, Bae K, 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.
84. Akada H, Akada S, Hutchison RE, Sakamoto K, Wagner KU, Mohi G. Critical role of Jak2 in the maintenance and function of adult hematopoietic stem cells. Stem Cells. 2014;32(7):1878-1889.
85. Grisouard J, Hao-Shen H, Dirnhofer S, Wagner KU, Skoda RC. Selective deletion of Jak2 in adult mouse hematopoietic cells leads to lethal anemia and thrombocytopenia. Haematologica. 2014;99(4):e52-e54.
86. Koppikar P, Bhagwat N, Kilpivaara O, et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature. 2012;489(7414):155-159.
87. Weigert O, Lane AA, Bird L, et al. Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition. J Exp Med. 2012;209(2):259-273.
88. Deshpande A, Reddy MM, Schade GO, et al. Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms. Leukemia. 2012;26(4):708-715.
89. Marubayashi S, Koppikar P, Taldone T, et al. HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans. J Clin Invest. 2010;120(10):3578-3593.
90. Bhagwat N, Koppikar P, Keller M, et al. Improved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms. Blood. 2014;123(13):2075-2083.
91. Bellucci S, Harousseau JL, Brice P, Tobelem G. Treatment of essential thrombocythaemia by alpha 2a interferon. Lancet. 1988;2(8617):960-961.
92. Silver RT. Recombinant interferon-alpha for treatment of polycythaemia vera. Lancet. 1988;2(8607):403.
93. Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112(8):3065-3072.
94. Quintas-Cardama A, Kantarjian H, Manshouri T, et al. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol. 2009;27(32):5418-5424.
95. Larsen TS, Moller MB, de Stricker K, et al. Minimal residual disease and normalization of the bone marrow after long-term treatment with alpha-interferon2b in polycythemia vera. A report on molecular response patterns in seven patients in sustained complete hematological remission. Hematology. 2009;14(6):331-334.
96. Ishii T, Xu M, Zhao Y, et al. Recurrence of clonal hematopoiesis after discontinuing pegylated recombinant interferon-alpha 2a in a patient with polycythemia vera. Leukemia. 2007;21(2):373-374.
97. Mullally A, Bruedigam C, Poveromo L, et al. Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-alpha in a murine model of polycythemia vera. Blood. 2013;121(18):3692-3702.