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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review JAK2 (janus kinase 2) Sabine Strehl Children's Cancer Research Institute, Kinderspitalgasse 6, A-1090 Vienna, Austria Published in Atlas Database: September 2005 Online updated version: http://AtlasGeneticsOncology.org/Genes/JAK98.html DOI: 10.4267/2042/38263 This article is an update of: Huret JL. JAK2 (janus kinase 2). Atlas Genet Cytogenet Oncol Haematol.1998;2(1):14. This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2006 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity PTK or TyrKc domain), and a tyrosine kinase-like domain JH2 (also termed STYKc). Hugo: JAK2 Location: 9p24 Expression Wide. Localisation Intracellular, possibly membrane associated. Function Protein tyrosine kinase of the non-receptor type that associates with the intracellular domains of cytokine receptors; JAK2 is the predominant JAK kinase activated in response to several growth factors and cytokines such as IL-3, GM-CSF and erythropoietin; it has been found to be constitutively associated with the prolactin receptor and is required for responses to gamma interferon. Homology JAK2 belongs to the janus kinase subfamily; so far four mammalian JAKs have been identified (JAK1, JAK2, JAK3, and TYK2); human JAK2 is >90% identical to the mouse and the rat JAK2 homologs. JAK2 (9p24) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Mutations DNA/RNA Somatic Description A high proportion (>50%) of patients with myeloproliferative disorders (MPD; (polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis - see below) carry a dominant gain-offunction V617F mutation in the JH2 kinase-like domain of JAK2. This mutation leads to deregulation of the kinase activity, and thus to constitutive tyrosine phosphorylation activity. The incidence of the V617F mutation in different studies ranges from 65-97% in polycythemia vera, from 41-57% in patients with essential thrombocythemia, and from 23-95% in 25 exons spanning roughly 140 kb of genomic DNA; 5402 bp pre-mRNA; 6 different transcripts, putatively encoding 4 different protein isoforms. Protein Description 1132 amino acids; 130,7 kDa; JAK2 contains a central Src homology 2 (SH2) domain, and two C-terminal domains: a tyrosine kinase domain JH1 (also termed Atlas Genet Cytogenet Oncol Haematol. 2006;10(1) 3 JAK2 (janus kinase 2) Strehl S patients with idiopathic myelofibrosis. In MPD the mutation is heterozygous in most patients and homozygous only in a minor subset. Mitotic recombination probably causes both 9p LOH and the transition from heterozygosity to homozygosity. The same mutation was also found in roughly 20% of Phnegative atypical CML, in more than 10% of CMML, in about 15% of patients with megakaryocytic AML (AML M7), and 1/5 patients with juvenile myelomonocytic leukemia (JMML). The V617F mutation seems to occur exclusively in hematopietic malignancies of the myeloid lineage. Hybrid/Mutated Gene 5' ETV6 - 3' JAK2 Abnormal Protein In the atypical CML the N-terminal HLH of ETV6 is fused to the tyrosine kinase C-terminal domains (JH2 and JH1) of JAK2; in the B-ALL the same ETV6 domain is fused to part of the JH2 and the complete JH1 domain, and in the T-ALL case to the JH1 domain. Oncogenesis It may be speculated that the HLH domain of ETV6 provides a dimerization interface to the kinase domain of JAK2, which activates JAK2; ETV6-JAK2 transgenic mice - generated using a T-ALL specific fusion construct - develop fatal CD8+ acute T-cell leukemia. Implicated in t(8;9)(p21-22;p24)/acute leukaemias → PCM1-JAK2 t(9;22)(p24;q11.2)/MPD→ JAK2-BCR Disease Myeloid and lymphoid malignancies; predominantly atypical CML, but also found in chronic eosinophilic leukemia (CEL), (secondary) AML, and MDS/MPD; thirteen cases described to date, all male, except for one childhood female case with erythroid leukemia with multiple bone tumors. Prognosis Highly variable; allogeneic stem cell transplantation may be the only curative treatment. Hybrid/Mutated Gene 5’ PCM1 - 3’ JAK2; only in some cases the reciprocal 5’ JAK2 - 3’ PCM1 is present. Abnormal Protein Almost the entire PCM1 protein containing multiple coiled-coil domains is fused to the tyrosine kinase Cterminal domains (JH2 and JH1) of JAK2. Oncogenesis Dimerization or oligomerization of the PCM1-JAK2 chimera through one or more of the coiled-coil motifs of PCM1 probably results in the constitutive activation of the tyrosine kinase domain of JAK2. Disease Atypical CML; only one case described to date. Hybrid/Mutated Gene 5’ BCR - 3’ JAK2; absence of the reciprocal 5’ JAK2 3’ BCR. Abnormal Protein The N-terminal coiled-coil domain of BCR is fused to the JH1 tyrosine kinase C-terminal domain of JAK2. Oncogenesis Constitutive activation of the tyrosine kinase domain of JAK2 mediated through oligomerization through the coiled-coil domain of BCR. Polycythemia vera/Essential thrombocythemia/Idiopathic thrombocythemia/Idiopathic myelofibrosis Note: the V617F mutation in JAK2 could form the basis for a new molecular classification of myeloproliferative disorders. Disease Chronic myeloproliferative syndromes. Oncogenesis A significant percentage of patients with myeloproliferative disorders carries a dominant gain of function V617F mutation in JAK2; this mutation seems to lead to deregulation of the kinase activity of JAK2, and thus to constitutive tyrosine phosphorylation activity, providing hematopoietic cells with a proliferative and survival advantage. t(9;12)(p24;p13) acute leukaemias → JAK2/ETV6 Disease Myeloid and lymphoid leukemias; only three cases described to date; one case each: childhood T-ALL, pre B-ALL, atypical CML. Prognosis Unknown. Atlas Genet Cytogenet Oncol Haematol. 2006;10(1) 4 JAK2 (janus kinase 2) Strehl S Goerttler PS, Steimle C, März E, Johansson PL, Andreasson B, Griesshammer M, Gisslinger H, Heimpel H, Pahl HL. The Jak2V617F mutation, PRV-1 overexpression and EEC formation define a similar cohort of MPD patients. Blood 2005;Jun 28; 106(8):2862-2864. Breakpoints Griesinger F, Hennig H, Hillmer F, Podleschny M, Steffens R, Pies A, Wormann B, Haase D, Bohlander SK. A BCR-JAK2 fusion gene as the result of a t(9;22)(p24;q11.2) translocation in a patient with a clinically typical chronic myeloid leukemia. Genes Chromosomes Cancer 2005;44(3):329-333. James C, Ugo V, Le Couédic J-P, Staerk J, Delhommeau F, Lacout C, Garçon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker,W. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;434:1144-1148. Jelinek J, Oki Y, Gharibyan V, Bueso-Ramos C, Prchal JT, Verstovsek S, Beran M, Estey E, Kantarjian HM, Issa JP. JAK2 mutation 1849G >T is rare in acute leukemias but can be found in CMML, Philadelphia-chromosome negative CML and megakaryocytic leukemia. Blood 2005;Jul 21; [Epub ahead of print]. References Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L, Score J, Seear R, Chase AJ, Grand FH, White H, Zoi C, Loukopoulos D, Terpos E, Vervessou EC, Schultheis B, Emig M, Ernst T, Lengfelder E, Hehlmann R, Hochhaus A, Oscier D, Silver RT, Reiter A, Cross NC. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 2005;106:2162-2168. Lacronique V, Boureux A, Valle VD, Poirel H, Quang CT, Mauchauffé M, Berthou C, Lessard M, Berger R, Ghysdael J, Bernard OA. A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science 1997;278:13091312. Peeters P, Raynaud SD, Cools J, Wlodarska I, Grosgeorge J, Philip P, Monpoux F, Van, Rompaey L, Baens M, Van den Berghe H, Marynen P. Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia. Blood 1997;90:2535-2540. Kralovics R, Passamonti F, Buser AS, Teo S-S, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC. A gain-offunction mutation of JAK2 in myeloproliferative disorders. New Eng J Med 2005;352:1779-1790. Kralovics R, Teo SS, Buser AS, Brutsche M, Tiedt R, Tichelli A, Passamonti F, Pietra D, Cazzola M, Skoda RC. Altered gene expression in myeloproliferative disorders correlates with activation of signaling by the V617F mutation of Jak2. Blood 2005;Aug 4; [Epub ahead of print]. Schwaller J, Frantsve J, Aster J, Williams IR, Tomasson MH, Ross TS, Peeters P, Van Rompaey L, Van Etten RA, Ilaria R Jr, Marynen P, Gilliland DG. Transformation of hematopoietic cell lines to growth-factor independence and induction of a fatal myelo- and lymphoproliferative disease in mice by retrovirally transduced TEL/JAK2 fusion genes. EMBO J 1998;17:53215333. Lasho TL, Mesa R, Gilliland DG, Tefferi A. Mutation studies in CD3+, CD19+ and CD34+ cell fractions in myeloproliferative disorders with homozygous JAK2(V617F) in granulocytes. Br J Haematol 2005;130:797-799. Carron C, Cormier F, Janin A, Lacronique V, Giovannini M, Daniel MT, Bernard O, Ghysdael J. TEL-JAK2 transgenic mice develop T-cell leukemia. Blood 2000;95:3891-3899. Levine RL, Loriaux M, Huntly BJ, Loh M, Beran M, Stoffregen E, Berger R, Clark JJ, Willis SG, Nguyen K, Flores N, Estey E, Gattermann N, Armstrong S, Look TA, Griffin JD, Bernard OA, Gilliland DG, Druker BJ, Deininger MW. The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood 2005;Aug 4; [Epub ahead of print]. Ho JM, Nguyen MH, Dierov JK, Badger KM, Beattie BK, Tartaro P, Haq R, Zanke BW, Carroll MP, Barber DL. TELJAK2 constitutively activates the extracellular signal-regulated kinase (ERK), stress-activated protein/Jun kinase (SAPK/JNK), and p38 signaling pathways. Blood 2002;100:1438-1448. Antonioli E, Guglielmelli P, Pancrazzi A, Bogani C, Verrucci M, Ponziani V, Longo G, Bosi A, Vannucchi AM. Clinical implications of the JAK2 V617F mutation in essential thrombocythemia. Leukemia 2005;19(10):1847-1849. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D'Andrea A, Fröhling S, Döhner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7:387-397. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR: Cancer Genome Project. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365:1054-1061. Bousquet M, Quelen C, De Mas V, Duchayne E, Roquefeuil B, Delsol G, Laurent G, Dastugue N, Brousset P. The t(8;9)(p22;p24) translocation in atypical chronic myeloid leukaemia yields a new PCM1-JAK2 fusion gene. Oncogene 2005;Aug 8; [Epub ahead of print]. Johan MF, Goodeve AC, Bowen DT, Frew ME, Reilly JT. JAK2 V617F Mutation is uncommon in chronic myelomonocytic leukaemia. Br J Haematol 2005;130:968. Frohling S, Scholl C, Gilliland DG, Levine RL. Genetics of myeloid malignancies: pathogenetic and clinical implications. J Clin Oncol 2005;23:6285-6295. Murati A, Gelsi-Boyer V, Adélaïde J, Pérot C, Talmant P, Giraudier S, Lodé L, Letessier A, Delaval B, Brunel V, Imbert M, Garand R, Xerri L, Birnbaum D, Mozziconacci MJ, Chaffanet M. PCM1-JAK2 fusion in myeloproliferative Atlas Genet Cytogenet Oncol Haematol. 2006;10(1) Mahon FX. JAK the trigger. Oncogene 2005;Jul 4; [Epub ahead of print]. 5 JAK2 (janus kinase 2) disorders and acute erythroid leukemia translocation. Leukemia 2005;19(9):1692-1696. Strehl S with t(8;9) Sulong S, Case M, Minto L, Wilkins B, Hall A, Irving J. The V617F mutation in Jak2 is not found in childhood acute lymphoblastic leukaemia. Br J Haematol 2005;130:964-965. Pesu M, O'shea J, Hennighausen L, Silvennoinen O. Identification of an acquired mutation in jak2 provides molecular insights into the pathogenesis of myeloproliferative disorders. Mol Interv 2005;5:211-215. Tefferi A, Gilliland DG. The JAK2V617F tyrosine kinase mutation in myeloproliferative disorders: status report and immediate implications for disease classification and diagnosis. Mayo Clin Proc 2005;80:947-958. (Review). Reiter A, Walz C, Watmore A, Schoch C, Blau I, Schlegelberger B, Berger U, Telford N, Aruliah S, Yin JA, Vanstraelen D, Barker HF, Taylor PC, O'Driscoll A, Benedetti F, Rudolph C, Kolb HJ, Hochhaus A, Hehlmann R, Chase A, Cross NC. The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2. Cancer Res 2005;65:2662-2667. Tefferi A, Gilliland DG. JAK2 in Myeloproliferative Disorders is Not Just Another Kinase. Cell Cycle 2005;4(8):1053-1056. Tono C, Xu G, Toki T, Takahashi Y, Sasaki S, Terui K, Ito E. JAK2 Val617Phe activating tyrosine kinase mutation in juvenile myelomonocytic leukemia. Leukemia 2005;19(10):1843-1844. Shannon K, Van Etten RA. JAKing up hematopoietic proliferation. Cancer Cell 2005;7:291-293. Zhao R, Xing S, Li Z, Fu X, Li Q, Krantz SB, Zhao ZJ. Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem 2005;280:22788-22792. Steensma DP, Dewald GW, Lasho TL, Powell HL, McClure RF, Levine RL, Gilliland DG, Tefferi A. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both 'atypical' myeloproliferative disorders and myelodysplastic syndromes. Blood 2005;106:1207-1209. This article should be referenced as such: Strehl S. JAK2 (janus kinase 2). Atlas Genet Cytogenet Oncol Haematol.2006;10(1):3-6. Atlas Genet Cytogenet Oncol Haematol. 2006;10(1) 6