Myeloproliferative Neoplasms: JAK2 Signaling Pathway as a Central Target for Therapy

Spivak, 2004, The chronic myeloproliferative disorders: clonality and clinical heterogeneity, Semin Hematol, 41, 1, 10.1053/j.seminhematol.2004.02.011 Baxter, 2005, Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders, Lancet, 365, 1054, 10.1016/S0140-6736(05)74230-6 James, 2005, A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera, Nature, 434, 1144, 10.1038/nature03546 Kralovics, 2005, A gain-of-function mutation of JAK2 in myeloproliferative disorders, N Engl J Med, 352, 1779, 10.1056/NEJMoa051113 Levine, 2005, Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis, Cancer Cell, 7, 387, 10.1016/j.ccr.2005.03.023 Akada, 2010, Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera-like disease, Blood, 115, 3589, 10.1182/blood-2009-04-215848 Hasan, 2013, JAK2V617F expression in mice amplifies early hematopoietic cells and gives them a competitive advantage that is hampered by IFNalpha, Blood, 122, 1464, 10.1182/blood-2013-04-498956 Lacout, 2006, JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis, Blood, 108, 1652, 10.1182/blood-2006-02-002030 Tiedt, 2008, Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice, Blood, 111, 3931, 10.1182/blood-2007-08-107748 Scott, 2006, Progenitors homozygous for the V617F mutation occur in most patients with polycythemia vera, but not essential thrombocythemia, Blood, 108, 2435, 10.1182/blood-2006-04-018259 Chen, 2010, Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling, Cancer Cell, 18, 524, 10.1016/j.ccr.2010.10.013 Yan, 2012, Critical requirement for Stat5 in a mouse model of polycythemia vera, Blood, 119, 3539, 10.1182/blood-2011-03-345215 Scott, 2007, JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis, N Engl J Med, 356, 459, 10.1056/NEJMoa065202 Villeval, 1997, High thrombopoietin production by hematopoietic cells induces a fatal myeloproliferative syndrome in mice, Blood, 90, 4369, 10.1182/blood.V90.11.4369 Pikman, 2006, MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia, PLoS Med, 3, e270, 10.1371/journal.pmed.0030270 Staerk, 2006, An amphipathic motif at the transmembrane-cytoplasmic junction prevents autonomous activation of the thrombopoietin receptor, Blood, 107, 1864, 10.1182/blood-2005-06-2600 Pardanani, 2006, MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients, Blood, 108, 3472, 10.1182/blood-2006-04-018879 Ding, 2004, Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin, Blood, 103, 4198, 10.1182/blood-2003-10-3471 Oh, 2010, Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms, Blood, 116, 988, 10.1182/blood-2010-02-270108 Tong, 2005, Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways, Blood, 105, 4604, 10.1182/blood-2004-10-4093 Pardanani, 2010, LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations, Leukemia, 24, 1713, 10.1038/leu.2010.163 Velazquez, 2002, Cytokine signaling and hematopoietic homeostasis are disrupted in Lnk-deficient mice, J Exp Med, 195, 1599, 10.1084/jem.20011883 Grand, 2009, Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms, Blood, 113, 6182, 10.1182/blood-2008-12-194548 Schwaab, 2012, Activating CBL mutations are associated with a distinct MDS/MPN phenotype, Ann Hematol, 91, 1713, 10.1007/s00277-012-1521-3 Nangalia, 2013, Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2, N Engl J Med, 369, 2391, 10.1056/NEJMoa1312542 Klampfl, 2013, Somatic mutations of calreticulin in myeloproliferative neoplasms, N Engl J Med, 369, 2379, 10.1056/NEJMoa1311347 Michalak, 2009, Calreticulin, a multi-process calcium-buffering chaperone of the endoplasmic reticulum, Biochem J, 417, 651, 10.1042/BJ20081847 Rotunno, 2014, Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia, Blood, 123, 1552, 10.1182/blood-2013-11-538983 Rumi, 2014, JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes, Blood, 123, 1544, 10.1182/blood-2013-11-539098 Hasan, 2014, Use of the 46/1 haplotype to model JAK2 clonal architecture in PV patients: clonal evolution and impact of IFNα treatment, Leukemia, 28, 460, 10.1038/leu.2013.303 Kralovics, 1997, The erythropoietin receptor gene is not linked with the polycythemia phenotype in a family with autosomal dominant primary polycythemia, Proc Assoc Am Physicians, 109, 580 Kralovics, 2001, Genetic heterogeneity of primary familial and congenital polycythemia, Am J Hematol, 68, 115, 10.1002/ajh.1162 Sulahian, 2009, Ligand-induced EpoR internalization is mediated by JAK2 and p85 and is impaired by mutations responsible for primary familial and congenital polycythemia, Blood, 113, 5287, 10.1182/blood-2008-09-179572 Teofili, 2011, Advances in understanding the pathogenesis of familial thrombocythaemia, Br J Haematol, 152, 701, 10.1111/j.1365-2141.2010.08500.x El-Harith, 2009, Familial thrombocytosis caused by the novel germ-line mutation p.Pro106Leu in the MPL gene, Br J Haematol, 144, 185, 10.1111/j.1365-2141.2008.07430.x Vilaine, 2012, Germline MPLW515R mutation in a family with isolated thrombocytosis, 54nd Annual Meeting of the American Society of Hematology (ASH) Kondo, 1998, Familial essential thrombocythemia associated with one-base deletion in the 5′-untranslated region of the thrombopoietin gene, Blood, 92, 1091, 10.1182/blood.V92.4.1091 Wiestner, 1998, An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia, Nat Genet, 18, 49, 10.1038/ng0198-49 Mead, 2013, Impact of isolated germline JAK2V617I mutation on human hematopoiesis, Blood, 121, 4156, 10.1182/blood-2012-05-430926 Rumi, 2014, A novel germline JAK2 mutation in familial myeloproliferative neoplasms, Am J Hematol, 89, 117, 10.1002/ajh.23614 Etheridge, 2014, A novel activating, germline JAK2 mutation, JAK2R564Q, causes familial essential thrombocytosis, Blood, 123, 1059, 10.1182/blood-2012-12-473777 Marty, 2014, Germline JAK2 mutations in the kinase domain are responsible for hereditary thrombocytosis and are resistant to JAK2 and HSP90 inhibitors, Blood, 123, 1372, 10.1182/blood-2013-05-504555 Plo, 2009, An activating mutation in the CSF3R gene induces a hereditary chronic neutrophilia, J Exp Med, 206, 1701, 10.1084/jem.20090693 Maxson, 2013, Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML, N Engl J Med, 368, 1781, 10.1056/NEJMoa1214514 Tahiliani, 2009, Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1, Science, 324, 930, 10.1126/science.1170116 Delhommeau, 2009, Mutation in TET2 in myeloid cancers, N Engl J Med, 360, 2289, 10.1056/NEJMoa0810069 Saint-Martin, 2009, Analysis of the ten-eleven translocation 2 (TET2) gene in familial myeloproliferative neoplasms, Blood, 114, 1628, 10.1182/blood-2009-01-197525 Moran-Crusio, 2011, Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation, Cancer Cell, 20, 11, 10.1016/j.ccr.2011.06.001 Quivoron, 2011, TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis, Cancer Cell, 20, 25, 10.1016/j.ccr.2011.06.003 Busque, 2012, Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis, Nat Genet, 44, 1179, 10.1038/ng.2413 Metzeler, 2011, TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study, J Clin Oncol, 29, 1373, 10.1200/JCO.2010.32.7742 Figueroa, 2010, Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation, Cancer Cell, 18, 553, 10.1016/j.ccr.2010.11.015 Vannucchi, 2013, Mutations and prognosis in primary myelofibrosis, Leukemia, 27, 1861, 10.1038/leu.2013.119 Abdel-Wahab, 2011, DNMT3A mutational analysis in primary myelofibrosis, chronic myelomonocytic leukemia and advanced phases of myeloproliferative neoplasms, Leukemia, 25, 1219, 10.1038/leu.2011.82 Challen, 2012, Dnmt3a is essential for hematopoietic stem cell differentiation, Nat Genet, 44, 23, 10.1038/ng.1009 Thol, 2011, Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia, J Clin Oncol, 29, 2889, 10.1200/JCO.2011.35.4894 Cho, 2006, 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, 17588, 10.1074/jbc.M512616200 Abdel-Wahab, 2012, ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression, Cancer Cell, 22, 180, 10.1016/j.ccr.2012.06.032 Gelsi-Boyer, 2009, Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia, Br J Haematol, 145, 788, 10.1111/j.1365-2141.2009.07697.x Abdel-Wahab, 2010, Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias, Cancer Res, 70, 447, 10.1158/0008-5472.CAN-09-3783 Abdel-Wahab, 2013, Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo, J Exp Med, 210, 2641, 10.1084/jem.20131141 Abdel-Wahab, 2011, Concomitant analysis of EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms, Leukemia, 25, 1200, 10.1038/leu.2011.58 Ernst, 2010, Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders, Nat Genet, 42, 722, 10.1038/ng.621 Guglielmelli, 2011, EZH2 mutational status predicts poor survival in myelofibrosis, Blood, 118, 5227, 10.1182/blood-2011-06-363424 Muto, 2013, Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders, J Exp Med, 210, 2627, 10.1084/jem.20131144 Yoshida, 2011, Frequent pathway mutations of splicing machinery in myelodysplasia, Nature, 478, 64, 10.1038/nature10496 Zhang, 2012, Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome, Blood, 119, 4480, 10.1182/blood-2011-11-390252 Tefferi, 2014, U2AF1 mutations in primary myelofibrosis are strongly associated with anemia and thrombocytopenia despite clustering with JAK2V617F and normal karyotype, Leukemia, 28, 431, 10.1038/leu.2013.286 Klampfl, 2011, Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression, Blood, 118, 167, 10.1182/blood-2011-01-331678 Harutyunyan, 2011, p53 Lesions in leukemic transformation, N Engl J Med, 364, 488, 10.1056/NEJMc1012718 Beer, 2010, Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm, Blood, 115, 2891, 10.1182/blood-2009-08-236596 Thoennissen, 2010, Prevalence and prognostic impact of allelic imbalances associated with leukemic transformation of Philadelphia chromosome-negative myeloproliferative neoplasms, Blood, 115, 2882, 10.1182/blood-2009-07-235119 Bhagwat, 2013, Sensitivity and resistance of JAK2 inhibitors to myeloproliferative neoplasms, Int J Hematol, 97, 695, 10.1007/s12185-013-1353-5 Harrison, 2012, JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis, N Engl J Med, 366, 787, 10.1056/NEJMoa1110556 Verstovsek, 2012, A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis, N Engl J Med, 366, 799, 10.1056/NEJMoa1110557 Verstovsek, 2012, Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls, Blood, 120, 1202, 10.1182/blood-2012-02-414631 Tefferi, 2011, Long-term outcome of treatment with ruxolitinib in myelofibrosis, N Engl J Med, 365, 1455, 10.1056/NEJMc1109555 Talpaz, 2013, Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts, J Hematol Oncol, 6, 81, 10.1186/1756-8722-6-81 Verstovsek, 2014, 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, 513, 10.1002/cncr.28441 Santos, 2010, Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis, Blood, 115, 1131, 10.1182/blood-2009-10-246363 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. Pardanani, 2013, Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis, Leukemia, 27, 1322, 10.1038/leu.2013.71 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. Koppikar, 2010, Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis, Blood, 115, 2919, 10.1182/blood-2009-04-218842 Jaekel, 2014, Allogeneic hematopoietic cell transplantation for myelofibrosis in patients pretreated with the JAK1 and JAK2 inhibitor ruxolitinib, Bone Marrow Transplant, 49, 179, 10.1038/bmt.2013.173 Tefferi, 2012, Challenges facing JAK inhibitor therapy for myeloproliferative neoplasms, N Engl J Med, 366, 844, 10.1056/NEJMe1115119 Deshpande, 2012, Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms, Leukemia, 26, 708, 10.1038/leu.2011.255 Weigert, 2012, Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition, J Exp Med, 209, 259, 10.1084/jem.20111694 Koppikar, 2012, Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy, Nature, 489, 155, 10.1038/nature11303 Gabler, 2013, JAK2 mutants (eg, JAK2V617F) and their importance as drug targets in myeloproliferative neoplasms, JAKSTAT, 2, e25025 Dusa, 2010, JAK2 V617F constitutive activation requires JH2 residue F595: a pseudokinase domain target for specific inhibitors, PLoS One, 5, e11157, 10.1371/journal.pone.0011157 Bandaranayake, 2012, Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F, Nat Struct Mol Biol, 19, 754, 10.1038/nsmb.2348 Marubayashi, 2010, HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans, J Clin Invest, 120, 3578, 10.1172/JCI42442 Chiosis, 2001, 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, 289, 10.1016/S1074-5521(01)00015-1 Fiskus, 2011, 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, 7347, 10.1158/1078-0432.CCR-11-1541 Guerini, 2008, The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2(V617F), Leukemia, 22, 740, 10.1038/sj.leu.2405049 Wang, 2009, Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells, Blood, 114, 5024, 10.1182/blood-2009-05-222133 Evrot, 2013, JAK1/2 and pan-deacetylase inhibitor combination therapy yields improved efficacy in preclinical mouse models of JAK2V617F-driven disease, Clin Cancer Res, 19, 6230, 10.1158/1078-0432.CCR-13-0905 Mascarenhas, 2013, 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, 68, 10.1111/bjh.12220 DeAngelo, 2013, 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, 326, 10.1111/bjh.12384 Wang, 2008, Enhanced histone deacetylase enzyme activity in primary myelofibrosis, Leuk Lymphoma, 49, 2321, 10.1080/10428190802527699 Kovacs, 2005, HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor, Mol Cell, 18, 601, 10.1016/j.molcel.2005.04.021 Garcon, 2006, Constitutive activation of STAT5 and Bcl-xL overexpression can induce endogenous erythroid colony formation in human primary cells, Blood, 108, 1551, 10.1182/blood-2005-10-009514 Nelson, 2011, The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors, Blood, 117, 3421, 10.1182/blood-2009-11-255232 Bar-Natan, 2012, Dual inhibition of Jak2 and STAT5 enhances killing of myeloproliferative neoplasia cells, Leukemia, 26, 1407, 10.1038/leu.2011.338 Pecquet, 2010, Induction of myeloproliferative disorder and myelofibrosis by thrombopoietin receptor W515 mutants is mediated by cytosolic tyrosine 112 of the receptor, Blood, 115, 1037, 10.1182/blood-2008-10-183558 Choong, 2013, Combination treatment for myeloproliferative neoplasms using JAK and pan-class I PI3K inhibitors, J Cell Mol Med, 17, 1397, 10.1111/jcmm.12156 Khan, 2013, AKT is a therapeutic target in myeloproliferative neoplasms, Leukemia, 27, 1882, 10.1038/leu.2013.167 Bartalucci, 2013, Rationale for targeting the PI3K/Akt/mTOR pathway in myeloproliferative neoplasms, Clin Lymphoma Myeloma Leuk, 13, S307, 10.1016/j.clml.2013.07.011 Bartalucci, 2013, Co-targeting the PI3K/mTOR and JAK2 signalling pathways produces synergistic activity against myeloproliferative neoplasms, J Cell Mol Med, 17, 1385, 10.1111/jcmm.12162 Guglielmelli, 2011, Safety and efficacy of everolimus, an mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis, Blood, 118, 2069, 10.1182/blood-2011-01-330563 Nakatake, 2012, JAK2(V617F) negatively regulates p53 stabilization by enhancing MDM2 via La expression in myeloproliferative neoplasms, Oncogene, 31, 1323, 10.1038/onc.2011.313 Lu, 2012, 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, 3098, 10.1182/blood-2012-02-410712 Lu, 2010, Treatment with the Bcl-xL inhibitor ABT-737 in combination with interferon alpha specifically targets JAK2V617F-positive polycythemia vera hematopoietic progenitor cells, Blood, 116, 4284, 10.1182/blood-2010-04-279125 Waibel, 2013, 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, 1047, 10.1016/j.celrep.2013.10.038 Gautier, 2012, The cell cycle regulator CDC25A is a target for JAK2V617F oncogene, Blood, 119, 1190, 10.1182/blood-2011-01-327742 Wernig, 2008, 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, 3751, 10.1182/blood-2007-07-102186 Walz, 2006, Activated Jak2 with the V617F point mutation promotes G1/S phase transition, J Biol Chem, 281, 18177, 10.1074/jbc.M600064200 Nieborowska-Skorska, 2012, Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors, Blood, 119, 4253, 10.1182/blood-2011-10-385658 Marty, 2013, A role for reactive oxygen species in JAK2 V617F myeloproliferative neoplasm progression, Leukemia, 27, 2187, 10.1038/leu.2013.102 Hurtado-Nedelec, 2013, Increased reactive oxygen species production and p47phox phosphorylation in neutrophils from myeloproliferative disorders patients with JAK2 (V617F) mutation, Haematologica, 98, 1517, 10.3324/haematol.2012.082560 Kiladjian, 2008, Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera, Blood, 112, 3065, 10.1182/blood-2008-03-143537 Kiladjian, 2006, High molecular response rate of polycythemia vera patients treated with pegylated interferon alpha-2a, Blood, 108, 2037, 10.1182/blood-2006-03-009860 Mullally, 2013, Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-alpha in a murine model of polycythemia vera, Blood, 121, 3692, 10.1182/blood-2012-05-432989 Lu, 2010, Interferon-alpha targets JAK2V617F-positive hematopoietic progenitor cells and acts through the p38 MAPK pathway, Exp Hematol, 38, 472, 10.1016/j.exphem.2010.03.005 Quintas-Cardama, 2013, Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon alpha-2a, Blood, 122, 893, 10.1182/blood-2012-07-442012 Essers, 2009, IFNalpha activates dormant haematopoietic stem cells in vivo, Nature, 458, 904, 10.1038/nature07815 Mehrotra, 2013, Essential role for the Mnk pathway in the inhibitory effects of type I interferons on myeloproliferative neoplasm (MPN) precursors, J Biol Chem, 288, 23814, 10.1074/jbc.M113.476192 Kiladjian, 2010, Clonal analysis of erythroid progenitors suggests that pegylated interferon alpha-2a treatment targets JAK2V617F clones without affecting TET2 mutant cells, Leukemia, 24, 1519, 10.1038/leu.2010.120 Smith, 2010, The potential role of epigenetic therapy in multiple myeloma, Br J Haematol, 148, 702, 10.1111/j.1365-2141.2009.07976.x Liu, 2011, JAK2V617F-mediated phosphorylation of PRMT5 downregulates its methyltransferase activity and promotes myeloproliferation, Cancer Cell, 19, 283, 10.1016/j.ccr.2010.12.020