Myeloproliferative neoplasms: JAK2 signaling pathway as a central target for therapy

Clinical Lymphoma, Myeloma and Leukemia

Volumn 14, Issue , 2014, Pages S23-S35

  Pasquier, Florence ^a,b   Cabagnols, Xenia ^a,b   Secardin, Lise ^a,b   Plo, Isabelle ^a,b   Vainchenker, William ^a,b  

^a INSTITUT GUSTAVE ROUSSY   (France)

^b Equipe Labellisée Ligue Nationale Contre le Cancer   (France)

Author keywords

Calreticulin; Clinical management; Inhibitors; MPL; Pathogenesis

Indexed keywords

ADENOSINE TRIPHOSPHATE; CALRETICULIN; CYTOKINE RECEPTOR; JANUS KINASE 2; JANUS KINASE 2 INHIBITOR; STAT PROTEIN; ANTINEOPLASTIC AGENT; PROTEIN KINASE INHIBITOR;

CANCER GROWTH; CANCER PROGNOSIS; CONFERENCE PAPER; EPIGENETICS; ERYTHROCYTOSIS; GENE MUTATION; GENETIC HETEROGENEITY; GENOME ANALYSIS; GERMLINE MUTATION; HUMAN; JAK2 GENE; MYELOID METAPLASIA; MYELOPROLIFERATIVE NEOPLASM; NEUTROPHILIA; NONHUMAN; ONCOGENE; PATHOGENESIS; PHENOTYPE; POLYCYTHEMIA VERA; RNA SPLICING; SH2B3 GENE; SIGNAL TRANSDUCTION; THROMBOCYTOSIS; THROMBOTIC THROMBOCYTOPENIC PURPURA; ANIMAL; DRUG EFFECTS; ENZYME ACTIVATION; GENETICS; METABOLISM; MOLECULARLY TARGETED THERAPY; MUTATION; MYELOPROLIFERATIVE DISORDERS;

ANIMALS; ANTINEOPLASTIC AGENTS; ENZYME ACTIVATION; HUMANS; JANUS KINASE 2; MOLECULAR TARGETED THERAPY; MUTATION; MYELOPROLIFERATIVE DISORDERS; PROTEIN KINASE INHIBITORS; SIGNAL TRANSDUCTION;

EID: 84926321462     PISSN: 21522650     EISSN: 21522669     Source Type: Journal    
DOI: 10.1016/j.clml.2014.06.014     Document Type: Conference Paper

References (131)

1. J.L. Spivak The chronic myeloproliferative disorders: clonality and clinical heterogeneity Semin Hematol 41 2004 1 5
2. E.J. Baxter, L.M. Scott, P.J. Campbell, and et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders Lancet 365 2005 1054 1061
3. C. James, V. Ugo, J.P. Le Couedic, and et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera Nature 434 2005 1144 1148
4. R. Kralovics, F. Passamonti, A.S. Buser, and et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders N Engl J Med 352 2005 1779 1790
5. R.L. Levine, M. Wadleigh, J. Cools, and et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis Cancer Cell 7 2005 387 397
6. H. Akada, D. Yan, H. Zou, and et al. Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera-like disease Blood 115 2010 3589 3597
7. S. Hasan, C. Lacout, C. Marty, and et al. JAK2V617F expression in mice amplifies early hematopoietic cells and gives them a competitive advantage that is hampered by IFNalpha Blood 122 2013 1464 1477
8. C. Lacout, D.F. Pisani, M. Tulliez, and et al. JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis Blood 108 2006 1652 1660
9. R. Tiedt, H. Hao-Shen, M.A. Sobas, and et al. Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice Blood 111 2008 3931 3940
10. L.M. Scott, M.A. Scott, P.J. Campbell, and et al. Progenitors homozygous for the V617F mutation occur in most patients with polycythemia vera, but not essential thrombocythemia Blood 108 2006 2435 2437
11. E. Chen, P.A. Beer, A.L. Godfrey, and et al. Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling Cancer Cell 18 2010 524 535
12. D. Yan, R.E. Hutchison, and G. Mohi Critical requirement for Stat5 in a mouse model of polycythemia vera Blood 119 2012 3539 3549
13. L.M. Scott, W. Tong, R.L. Levine, and et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis N Engl J Med 356 2007 459 468
14. J.L. Villeval, K. Cohen-Solal, M. Tulliez, and et al. High thrombopoietin production by hematopoietic cells induces a fatal myeloproliferative syndrome in mice Blood 90 1997 4369 4383
15. Y. Pikman, B.H. Lee, T. Mercher, and et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia PLoS Med 3 2006 e270
16. J. Staerk, C. Lacout, T. Sato, and et al. An amphipathic motif at the transmembrane-cytoplasmic junction prevents autonomous activation of the thrombopoietin receptor Blood 107 2006 1864 1871
17. A.D. Pardanani, R.L. Levine, T. Lasho, and et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients Blood 108 2006 3472 3476
18. J. Ding, H. Komatsu, A. Wakita, and 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 103 2004 4198 4200
19. S.T. Oh, E.F. Simonds, C. Jones, and et al. Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms Blood 116 2010 988 992
20. W. Tong, J. Zhang, and H.F. Lodish Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways Blood 105 2005 4604 4612
21. A. Pardanani, T. Lasho, C. Finke, and et al. LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations Leukemia 24 2010 1713 1718
22. L. Velazquez, A.M. Cheng, H.E. Fleming, and et al. Cytokine signaling and hematopoietic homeostasis are disrupted in Lnk-deficient mice J Exp Med 195 2002 1599 1611
23. F.H. Grand, C.E. Hidalgo-Curtis, T. Ernst, and et al. Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms Blood 113 2009 6182 6192
24. J. Schwaab, T. Ernst, P. Erben, and et al. Activating CBL mutations are associated with a distinct MDS/MPN phenotype Ann Hematol 91 2012 1713 1720
25. J. Nangalia, C.E. Massie, E.J. Baxter, and et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2 N Engl J Med 369 2013 2391 2405
26. T. Klampfl, H. Gisslinger, A.S. Harutyunyan, and et al. Somatic mutations of calreticulin in myeloproliferative neoplasms N Engl J Med 369 2013 2379 2390
27. M. Michalak, J. Groenendyk, E. Szabo, and et al. Calreticulin, a multi-process calcium-buffering chaperone of the endoplasmic reticulum Biochem J 417 2009 651 666
28. G. Rotunno, C. Mannarelli, P. Guglielmelli, and et al. Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia Blood 123 2014 1552 1555
29. E. Rumi, D. Pietra, V. Ferretti, and et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes Blood 123 2014 1544 1551
30. S. Hasan, B. Cassinat, N. Droin, and et al. Use of the 46/1 haplotype to model JAK2 clonal architecture in PV patients: clonal evolution and impact of IFNα treatment Leukemia 28 2014 460 463
31. R. Kralovics, L. Sokol, E.H. Broxson Jr., and et al. The erythropoietin receptor gene is not linked with the polycythemia phenotype in a family with autosomal dominant primary polycythemia Proc Assoc Am Physicians 109 1997 580 585
32. R. Kralovics, and J.T. Prchal Genetic heterogeneity of primary familial and congenital polycythemia Am J Hematol 68 2001 115 121
33. R. Sulahian, O. Cleaver, and L.J. Huang Ligand-induced EpoR internalization is mediated by JAK2 and p85 and is impaired by mutations responsible for primary familial and congenital polycythemia Blood 113 2009 5287 5297
34. L. Teofili, and L.M. Larocca Advances in understanding the pathogenesis of familial thrombocythaemia Br J Haematol 152 2011 701 712
35. el-HA. El-Harith, C. Roesl, M. Ballmaier, and et al. Familial thrombocytosis caused by the novel germ-line mutation p.Pro106Leu in the MPL gene Br J Haematol 144 2009 185 194
36. M. Vilaine, V. Gourain, C. Cleyrat, and et al. Germline MPLW515R mutation in a family with isolated thrombocytosis 54nd Annual Meeting of the American Society of Hematology (ASH) 2012 Abstract 1764
37. T. Kondo, M. Okabe, M. Sanada, and et al. Familial essential thrombocythemia associated with one-base deletion in the 5′-untranslated region of the thrombopoietin gene Blood 92 1998 1091 1096
38. A. Wiestner, R.J. Schlemper, A.P. van der Maas, and et al. An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia Nat Genet 18 1998 49 52
39. A.J. Mead, O. Chowdhury, C. Pecquet, and et al. Impact of isolated germline JAK2V617I mutation on human hematopoiesis Blood 121 2013 4156 4165
40. E. Rumi, A.S. Harutyunyan, I. Casetti, and et al. A novel germline JAK2 mutation in familial myeloproliferative neoplasms Am J Hematol 89 2014 117 118
41. S.L. Etheridge, M.E. Cosgrove, V. Sangkhae, and et al. A novel activating, germline JAK2 mutation, JAK2R564Q, causes familial essential thrombocytosis Blood 123 2014 1059 1068
42. C. Marty, C. Saint Martin, C. Pecquet, and et al. Germline JAK2 mutations in the kinase domain are responsible for hereditary thrombocytosis and are resistant to JAK2 and HSP90 inhibitors Blood 123 2014 1372 1383
43. I. Plo, Y. Zhang, J.P. Le Couedic, and et al. An activating mutation in the CSF3R gene induces a hereditary chronic neutrophilia J Exp Med 206 2009 1701 1707
44. J.E. Maxson, J. Gotlib, D.A. Pollyea, and et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML N Engl J Med 368 2013 1781 1790
45. M. Tahiliani, K.P. Koh, Y. Shen, and et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1 Science 324 2009 930 935
46. F. Delhommeau, S. Dupont, V. Della Valle, and et al. Mutation in TET2 in myeloid cancers N Engl J Med 360 2009 2289 2301
47. C. Saint-Martin, G. Leroy, F. Delhommeau, and et al. Analysis of the ten-eleven translocation 2 (TET2) gene in familial myeloproliferative neoplasms Blood 114 2009 1628 1632
48. K. Moran-Crusio, L. Reavie, A. Shih, and et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation Cancer Cell 20 2011 11 24
49. C. Quivoron, L. Couronne, V. Della Valle, and et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis Cancer Cell 20 2011 25 38
50. L. Busque, J.P. Patel, M.E. Figueroa, and et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis Nat Genet 44 2012 1179 1181
51. K.H. Metzeler, K. Maharry, M.D. Radmacher, and et al. TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study J Clin Oncol 29 2011 1373 1381
52. M.E. Figueroa, O. Abdel-Wahab, C. Lu, and et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation Cancer Cell 18 2010 553 567
53. A.M. Vannucchi, T.L. Lasho, P. Guglielmelli, and et al. Mutations and prognosis in primary myelofibrosis Leukemia 27 2013 1861 1869
54. O. Abdel-Wahab, A. Pardanani, R. Rampal, and et al. DNMT3A mutational analysis in primary myelofibrosis, chronic myelomonocytic leukemia and advanced phases of myeloproliferative neoplasms Leukemia 25 2011 1219 1220
55. G.A. Challen, D. Sun, M. Jeong, and et al. Dnmt3a is essential for hematopoietic stem cell differentiation Nat Genet 44 2012 23 31
56. F. Thol, F. Damm, A. Ludeking, and et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia J Clin Oncol 29 2011 2889 2896
57. Y.S. Cho, E.J. Kim, U.H. Park, and et al. Additional sex comb-like 1 (ASXL1), in cooperation with SRC-1, acts as a ligand-dependent coactivator for retinoic acid receptor J Biol Chem 281 2006 17588 17598
58. O. Abdel-Wahab, M. Adli, L.M. LaFave, and et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression Cancer Cell 22 2012 180 193
59. V. Gelsi-Boyer, V. Trouplin, J. Adelaide, and et al. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia Br J Haematol 145 2009 788 800
60. O. Abdel-Wahab, T. Manshouri, J. Patel, and et al. Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias Cancer Res 70 2010 447 452
61. O. Abdel-Wahab, J. Gao, M. Adli, and et al. Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo J Exp Med 210 2013 2641 2659
62. O. Abdel-Wahab, A. Pardanani, J. Patel, and et al. Concomitant analysis of EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms Leukemia 25 2011 1200 1202
63. T. Ernst, A.J. Chase, J. Score, and et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders Nat Genet 42 2010 722 726
64. P. Guglielmelli, F. Biamonte, J. Score, and et al. EZH2 mutational status predicts poor survival in myelofibrosis Blood 118 2011 5227 5234
65. T. Muto, G. Sashida, M. Oshima, and et al. Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders J Exp Med 210 2013 2627 2639
66. K. Yoshida, M. Sanada, Y. Shiraishi, and et al. Frequent pathway mutations of splicing machinery in myelodysplasia Nature 478 2011 64 69
67. S.J. Zhang, R. Rampal, T. Manshouri, and et al. Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome Blood 119 2012 4480 4485
68. A. Tefferi, C.M. Finke, T.L. Lasho, and et al. U2AF1 mutations in primary myelofibrosis are strongly associated with anemia and thrombocytopenia despite clustering with JAK2V617F and normal karyotype Leukemia 28 2014 431 433
69. T. Klampfl, A. Harutyunyan, T. Berg, and et al. Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression Blood 118 2011 167 176
70. A. Harutyunyan, T. Klampfl, M. Cazzola, and et al. p53 Lesions in leukemic transformation N Engl J Med 364 2011 488 490
71. P.A. Beer, F. Delhommeau, J.P. LeCouedic, and et al. Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm Blood 115 2010 2891 2900
72. N.H. Thoennissen, U.O. Krug, D.H. Lee, and et al. Prevalence and prognostic impact of allelic imbalances associated with leukemic transformation of Philadelphia chromosome-negative myeloproliferative neoplasms Blood 115 2010 2882 2890
73. N. Bhagwat, R.L. Levine, and P. Koppikar Sensitivity and resistance of JAK2 inhibitors to myeloproliferative neoplasms Int J Hematol 97 2013 695 702
74. C. Harrison, J.J. Kiladjian, H.K. Al-Ali, and et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis N Engl J Med 366 2012 787 798
75. S. Verstovsek, R.A. Mesa, J. Gotlib, and et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis N Engl J Med 366 2012 799 807
76. S. Verstovsek, H.M. Kantarjian, Z. Estrov, and et al. Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls Blood 120 2012 1202 1209
77. A. Tefferi, M.R. Litzow, and A. Pardanani Long-term outcome of treatment with ruxolitinib in myelofibrosis N Engl J Med 365 2011 1455 1457
78. M. Talpaz, R. Paquette, L. Afrin, and et al. Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts J Hematol Oncol 6 2013 81
79. S. Verstovsek, F. Passamonti, A. Rambaldi, and et al. A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea Cancer 120 2014 513 520
80. F.P. Santos, H.M. Kantarjian, N. Jain, and et al. Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis Blood 115 2010 1131 1136
81. Moliterno AR, Hexner E, Roboz GJ, et al. An open-label study of CEP-701 in patients with JAK2 V617F-positive PV and ET: update of 39 enrolled patients. 51st Annual Meeting of the American Society of Hematology, New Orleans, LA. 2009; 114:313-314.
82. A. Pardanani, R.R. Laborde, T.L. Lasho, and et al. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis Leukemia 27 2013 1322 1327
83. Komrokji RS, Wadleigh M, Seymour JF, et al. Results of a phase 2 study of pacritinib (SB1518), a novel oral JAK2 inhibitor, in patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis. 53rd Annual Meeting and Exposition of the American Society of Hematology (ASH)/Symposium on the Basic Science of Hemostasis and Thrombosis 2011; 118:130-131.
84. P. Koppikar, O. Abdel-Wahab, C. Hedvat, and et al. Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis Blood 115 2010 2919 2927
85. N. Jaekel, G. Behre, A. Behning, and et al. Allogeneic hematopoietic cell transplantation for myelofibrosis in patients pretreated with the JAK1 and JAK2 inhibitor ruxolitinib Bone Marrow Transplant 49 2014 179 184
86. A. Tefferi Challenges facing JAK inhibitor therapy for myeloproliferative neoplasms N Engl J Med 366 2012 844 846
87. A. Deshpande, M.M. Reddy, G.O. Schade, and et al. Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms Leukemia 26 2012 708 715
88. O. Weigert, A.A. Lane, L. Bird, and et al. Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition J Exp Med 209 2012 259 273
89. P. Koppikar, N. Bhagwat, O. Kilpivaara, and et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy Nature 489 2012 155 159
90. K. Gabler, I. Behrmann, and C. Haan JAK2 mutants (eg, JAK2V617F) and their importance as drug targets in myeloproliferative neoplasms JAKSTAT 2 2013 e25025
91. A. Dusa, C. Mouton, C. Pecquet, and et al. JAK2 V617F constitutive activation requires JH2 residue F595: a pseudokinase domain target for specific inhibitors PLoS One 5 2010 e11157
92. R.M. Bandaranayake, D. Ungureanu, Y. Shan, and et al. Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F Nat Struct Mol Biol 19 2012 754 759
93. S. Marubayashi, P. Koppikar, T. Taldone, and et al. HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans J Clin Invest 120 2010 3578 3593
94. G. Chiosis, M.N. Timaul, B. Lucas, and et al. A small molecule designed to bind to the adenine nucleotide pocket of Hsp90 causes Her2 degradation and the growth arrest and differentiation of breast cancer cells Chem Biol 8 2001 289 299
95. W. Fiskus, S. Verstovsek, T. Manshouri, and et al. Heat shock protein 90 inhibitor is synergistic with JAK2 inhibitor and overcomes resistance to JAK2-TKI in human myeloproliferative neoplasm cells Clin Cancer Res 17 2011 7347 7358
96. V. Guerini, V. Barbui, O. Spinelli, and et al. The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2(V617F) Leukemia 22 2008 740 747
97. Y. Wang, W. Fiskus, D.G. Chong, and et al. Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells Blood 114 2009 5024 5033
98. E. Evrot, N. Ebel, V. Romanet, and et al. JAK1/2 and pan-deacetylase inhibitor combination therapy yields improved efficacy in preclinical mouse models of JAK2V617F-driven disease Clin Cancer Res 19 2013 6230 6241
99. J. Mascarenhas, M. Lu, T. Li, and et al. A phase I study of panobinostat (LBH589) in patients with primary myelofibrosis (PMF) and post-polycythaemia vera/essential thrombocythaemia myelofibrosis (post-PV/ET MF) Br J Haematol 161 2013 68 75
100. D.J. DeAngelo, R.A. Mesa, W. Fiskus, and et al. Phase II trial of panobinostat, an oral pan-deacetylase inhibitor in patients with primary myelofibrosis, post-essential thrombocythaemia, and post-polycythaemia vera myelofibrosis Br J Haematol 162 2013 326 335
101. J.C. Wang, C. Chen, T. Dumlao, and et al. Enhanced histone deacetylase enzyme activity in primary myelofibrosis Leuk Lymphoma 49 2008 2321 2327
102. J.J. Kovacs, P.J. Murphy, S. Gaillard, and et al. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor Mol Cell 18 2005 601 607
103. L. Garcon, C. Rivat, C. James, and et al. Constitutive activation of STAT5 and Bcl-xL overexpression can induce endogenous erythroid colony formation in human primary cells Blood 108 2006 1551 1554
104. E.A. Nelson, S.R. Walker, E. Weisberg, and et al. The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors Blood 117 2011 3421 3429
105. M. Bar-Natan, E.A. Nelson, S.R. Walker, and et al. Dual inhibition of Jak2 and STAT5 enhances killing of myeloproliferative neoplasia cells Leukemia 26 2012 1407 1410
106. C. Pecquet, J. Staerk, R. Chaligne, and et al. Induction of myeloproliferative disorder and myelofibrosis by thrombopoietin receptor W515 mutants is mediated by cytosolic tyrosine 112 of the receptor Blood 115 2010 1037 1048
107. M.L. Choong, C. Pecquet, V. Pendharkar, and et al. Combination treatment for myeloproliferative neoplasms using JAK and pan-class I PI3K inhibitors J Cell Mol Med 17 2013 1397 1409
108. I. Khan, Z. Huang, Q. Wen, and et al. AKT is a therapeutic target in myeloproliferative neoplasms Leukemia 27 2013 1882 1890
109. N. Bartalucci, P. Guglielmelli, and A.M. Vannucchi Rationale for targeting the PI3K/Akt/mTOR pathway in myeloproliferative neoplasms Clin Lymphoma Myeloma Leuk 13 suppl 2 2013 S307 S309
110. N. Bartalucci, L. Tozzi, C. Bogani, and et al. Co-targeting the PI3K/mTOR and JAK2 signalling pathways produces synergistic activity against myeloproliferative neoplasms J Cell Mol Med 17 2013 1385 1396
111. P. Guglielmelli, G. Barosi, A. Rambaldi, and et al. Safety and efficacy of everolimus, an mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis Blood 118 2011 2069 2076
112. M. Nakatake, B. Monte-Mor, N. Debili, and et al. JAK2(V617F) negatively regulates p53 stabilization by enhancing MDM2 via La expression in myeloproliferative neoplasms Oncogene 31 2012 1323 1333
113. M. Lu, X. Wang, Y. Li, and et al. Combination treatment in vitro with Nutlin, a small-molecule antagonist of MDM2, and pegylated interferon-alpha 2a specifically targets JAK2V617F-positive polycythemia vera cells Blood 120 2012 3098 3105
114. M. Lu, J. Wang, Y. Li, and et al. Treatment with the Bcl-xL inhibitor ABT-737 in combination with interferon alpha specifically targets JAK2V617F-positive polycythemia vera hematopoietic progenitor cells Blood 116 2010 4284 4287
115. M. Waibel, V.S. Solomon, D.A. Knight, and et al. Combined targeting of JAK2 and Bcl-2/Bcl-xL to cure mutant JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitors Cell Rep 5 2013 1047 1059
116. E.F. Gautier, M. Picard, C. Laurent, and et al. The cell cycle regulator CDC25A is a target for JAK2V617F oncogene Blood 119 2012 1190 1199
117. G. Wernig, J.R. Gonneville, B.J. Crowley, and 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 111 2008 3751 3759
118. C. Walz, B.J. Crowley, H.E. Hudon, and et al. Activated Jak2 with the V617F point mutation promotes G1/S phase transition J Biol Chem 281 2006 18177 18183
119. M. Nieborowska-Skorska, P.K. Kopinski, R. Ray, and et al. Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors Blood 119 2012 4253 4263
120. C. Marty, C. Lacout, N. Droin, and et al. A role for reactive oxygen species in JAK2 V617F myeloproliferative neoplasm progression Leukemia 27 2013 2187 2195
121. M. Hurtado-Nedelec, M.J. Csillag-Grange, T. Boussetta, and et al. Increased reactive oxygen species production and p47phox phosphorylation in neutrophils from myeloproliferative disorders patients with JAK2 (V617F) mutation Haematologica 98 2013 1517 1524
122. J.J. Kiladjian, B. Cassinat, S. Chevret, and et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera Blood 112 2008 3065 3072
123. J.J. Kiladjian, B. Cassinat, P. Turlure, and et al. High molecular response rate of polycythemia vera patients treated with pegylated interferon alpha-2a Blood 108 2006 2037 2040
124. A. Mullally, C. Bruedigam, L. Poveromo, and et al. Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-alpha in a murine model of polycythemia vera Blood 121 2013 3692 3702
125. M. Lu, W. Zhang, Y. Li, and et al. Interferon-alpha targets JAK2V617F-positive hematopoietic progenitor cells and acts through the p38 MAPK pathway Exp Hematol 38 2010 472 480
126. A. Quintas-Cardama, O. Abdel-Wahab, T. Manshouri, and et al. Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon alpha-2a Blood 122 2013 893 901
127. M.A. Essers, S. Offner, W.E. Blanco-Bose, and et al. IFNalpha activates dormant haematopoietic stem cells in vivo Nature 458 2009 904 908
128. S. Mehrotra, B. Sharma, S. Joshi, and et al. Essential role for the Mnk pathway in the inhibitory effects of type I interferons on myeloproliferative neoplasm (MPN) precursors J Biol Chem 288 2013 23814 23822
129. J.J. Kiladjian, A. Masse, B. Cassinat, and et al. Clonal analysis of erythroid progenitors suggests that pegylated interferon alpha-2a treatment targets JAK2V617F clones without affecting TET2 mutant cells Leukemia 24 2010 1519 1523
130. E.M. Smith, K. Boyd, and F.E. Davies The potential role of epigenetic therapy in multiple myeloma Br J Haematol 148 2010 702 713
131. F. Liu, X. Zhao, F. Perna, and et al. JAK2V617F-mediated phosphorylation of PRMT5 downregulates its methyltransferase activity and promotes myeloproliferation Cancer Cell 19 2011 283 294