JAK2 mutation and treatment of JAK2 inhibitors in Philadelphia chromosome-negative myeloproliferative neoplasms


Susanna Hilda Hutajulu(1*), Johan Kurnianda(2)

(*) Corresponding Author


The Philadelphia chromosome-negative (Ph-negative) myeloproliferative neoplasms (MPNs) polycythaemia vera (PV), essential thombocythaemia (ET) and primary myelofi brosis (PMF) are clonal disorders of multipotent haematopoietic progenitors. The genetic cause of these disorders was not fully defi ned until a somatic activating mutation in the JAK2 non-receptor tyrosine kinase, JAK2V617F, was identifi ed in most patients with PV and a considerable proportion of patients with ET and PMF. The discovery of JAK2 mutation has changed the molecular reclassification of MPNs and served as a genomic target for therapeutic implication. A number of JAK2 inhibitors have been developed and tested for MPNs. Several JAK2 inhibitors have reached the phases of clinical trial and included patients with intermediate-risk or high-risk MF. This population of MF is the best candidate for trials because currently it has no effective therapy besides patients’ poor survival. Considering all clinical data on Ph negative MPNs, JAK2 inhibitors have shown a clinical benefi t and reduced symptoms in the vast majority of MF cases. The most developed among JAK2 inhibitors is Ruxolitinib, which has demonstrated clinical improvement with well tolerated toxicities. However, JAK2 inhibitor was equally active in patients with and without JAK2 mutation. Other JAK2 inhibitors are less developed, but showed a similar clinical benefi t. Furthermore, its effect on the natural course of MPNs in treating patients needs to be investigated.

Keywords: myeloproliferative neoplasms – JAK2 mutation – JAK2 inhibitors.

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Spivak JL. The chronic myeloproliferative disorders: clonality and clinical heterogeneity. Semin Hematol. Apr 2004;41(2 Suppl 3):1-5.

Spivak JL, Barosi G, Tognoni G, et al. Chronic myeloproliferative disorders. Hematology Am Soc Hematol Educ Program. 2003:200-224.

Bartram CR, de Klein A, Hagemeijer A, et al. Translocation of c-ab1 oncogene correlates with the presence of a Philadelphia chromosome in

chronic myelocytic leukaemia. Nature. Nov 17-23 1983;306(5940):277-280.

Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell. Apr 22 1994;77(2):307-316.

Cools J, DeAngelo DJ, Gotlib 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. Mar 27 2003;348(13):1201-1214.

Longley BJ, Tyrrell L, Lu SZ, et al. Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nat Genet. Mar 1996; 12(3):312-314.

Ugo V, Marzac C, Teyssandier I, et al. Multiple signaling pathways are involved in erythropoietinindependent differentiation of erythroid progenitors in polycythemia vera. Exp Hematol. Feb 2004; 32(2):179-187.

Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofi brosis. Cancer Cell. Apr 2005; 7(4):387-397.

James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. Apr 28 2005;434(7037):1144-1148.

Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. Mar 19-25 2005;365(9464):1054-1061.

Kralovics R, Passamonti F, Buser AS, et al. A gainof-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. Apr 28 2005; 352(17):1779-1790.

Goldman JM. A unifying mutation in chronic myeloproliferative disorders. N Engl J Med. Apr 28 2005;352(17):1744-1746.

Vainchenker W, Dusa A, Constantinescu SN. JAKs in pathology: role of Janus kinases in hematopoietic malignancies and immunodefi ciencies. Semin Cell Dev Biol. Aug 2008;19(4):385-393.

Quintas-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the selective JAK1/2 inhibitor JAK2 mutation and treatment of JAK2 inhibitors in Philadelphia chromosome-negative myeloproliferative neoplasms 77 INCB018424: therapeutic implications for the

treatment of myeloproliferative neoplasms. Blood. Apr 15 2010; 115(15):3109-3117.

Zhao R, Xing S, Li Z, et al. Identifi cation of an acquired JAK2 mutation in polycythemia vera. J Biol Chem. Jun 17 2005;280(24):22788-22792.

Kralovics R, Guan Y, Prchal JT. Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera. Exp Hematol. Mar 2002;30(3):229-236.

Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. Sep 2007;7(9):673-683.

Khwaja A. The role of Janus kinases in haemopoiesis and haematological malignancy. Br J Haematol.Aug 2006;134(4):366-384.

Levine RL, Loriaux M, Huntly BJ, et al. The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood. Nov 15 2005;106(10):3377-3379.

Levine RL, Belisle C, Wadleigh M, 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 identifi es a subset of JAK2V617F-negative ET and MMM patients with clonal hematopoiesis. Blood. May 15 2006;107(10):4139-4141.

Campbell PJ, Scott LM, Baxter EJ, Bench AJ, Green AR, Erber WN. Methods for the detection of the JAK2 V617F mutation in human myeloproliferative disorders. Methods Mol Med. 2006;125:253-264.

Jones AV, Kreil S, Zoi K, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood. Sep 15 2005; 106(6):2162-2168.

Pardanani AD, Levine RL, Lasho T, et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood. Nov 15, 2006;108(10):3472-3476.

Hookham MB, Elliott J, Suessmuth Y, et al. The myeloproliferative disorder-associated JAK2 V617F mutant escapes negative regulation by

suppressor of cytokine signaling 3. Blood. Jun 1 2007;109(11):4924-4929.

Lucet IS, Fantino E, Styles M, et al. The structural basis of Janus kinase 2 inhibition by a potent and specifi c pan-Janus kinase inhibitor. Blood. Jan 1


Pardanani A, Hood J, Lasho T, et al. TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. Leukemia. Aug 2007; 21(8):1658-1668.

Van Etten RA, Koschmieder S, Delhommeau F, et al. The Ph-positive and Ph-negative myeloproliferative neoplasms: some topical pre-clinical and clinical issues. Haematologica. Apr 2011;96(4):590-601.

Bellido M, Te Boekhorst PA. JAK2 Inhibition: Reviewing a New Therapeutical Option in Myeloproliferative Neoplasms. Adv Hematol.2012;2012:535709.

Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and effi cacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofi brosis. N Engl J Med. Sep 16 2010;363(12):1117-1127.

Pardanani A, Gotlib JR, Jamieson C, et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol. Mar 1


Tyner JW, Bumm TG, Deininger J, et al. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes infl ammatory cytokines

in murine myeloproliferative neoplasms. Blood. Jun 24, 2010; 115(25):5232-5240.

Hexner EO, Serdikoff C, Jan M, 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. Jun 15 2008;111(12):5663-5671.

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. Oct 15 2008;112(8):3065-3072.

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. Nov 10 2009;27(32):5418-5424.

Elliott MA, Verstovsek S, Dingli D, et al. Monocytosis is an adverse prognostic factor for survival in younger patients with primary myelofi brosis. Leuk Res. Nov 2007;31(11):1503-1509.

Tefferi A, Cortes J, Verstovsek S, et al. Lenalidomide therapy in myelofi brosis with myeloid metaplasia. Blood. Aug 15 2006;108(4):1158-1164.

Pardanani A. JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials. Leukemia. Jan


Gangat N, Wolanskyj AP, McClure RF, et al. Risk stratification for survival and leukemic transformation in essential thrombocythemia: a

single institutional study of 605 patients. Leukemia. Feb 2007;21(2):270-276.

Gangat N, Strand J, Li CY, Wu W, Pardanani A, Tefferi A. Leucocytosis in polycythaemia vera predicts both inferior survival and leukaemic transformation. Br J Haematol. Aug 2007;138(3):354-358.

Passamonti F, Maffi oli M, Caramazza D, Cazzola M. Myeloproliferative neoplasms: from JAK2 mutations discovery to JAK2 inhibitor therapies. Oncotarget. Jun 2011;2(6):485-490.

Santos FP, Kantarjian HM, Jain N, et al. Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/ essential thrombocythemia myelofi brosis. Blood.Feb 11 2010;115(6):1131-1136.

Millecker L, Lennon PA, Verstovsek S, et al. Distinct patterns of cytogenetic and clinical progression in chronic myeloproliferative neoplasms with or without JAK2 or MPL mutations. Cancer Genet

Cytogenet. Feb 2010;197(1):1-7.

Guerini V, Barbui V, Spinelli O, et al. The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2(V617F). Leukemia. Apr 2008;22(4):740-747.

Shi J, Zhao Y, Ishii T, et al. Effects of chromatin modifying agents on CD34+ cells from patients with idiopathic myelofi brosis. Cancer Res. Jul 1 2007;67(13):6417-6424.

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. Nov 15 2006;108(10):3548-3555.

Quintas-Cardama A, Verstovsek S. New JAK2 inhibitors for myeloproliferative neoplasms. Expert Opin Investig Drugs. Jul 2011;20(7):961-972.

Agarwal MB. Clinical applications of molecular haematology: JAK2 in myeloproliferative disorders. J Assoc Physicians India. Jul 2007;55:507-510.

DOI: https://doi.org/10.22146/acta%20interna.5003

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