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Previous Volume 352:1779-1790 April 28, 2005 Number 17 Next

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ABSTRACT

Background Polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are clonal myeloproliferative disorders arising from a multipotent progenitor. The loss of heterozygosity (LOH) on the short arm of chromosome 9 (9pLOH) in myeloproliferative disorders suggests that 9p harbors a mutation that contributes to the cause of clonal expansion of hematopoietic cells in these diseases.

Methods We performed microsatellite mapping of the 9pLOH region and DNA sequencing in 244 patients with myeloproliferative disorders (128 with polycythemia vera, 93 with essential thrombocythemia, and 23 with idiopathic myelofibrosis).

Results Microsatellite mapping identified a 9pLOH region that included the Janus kinase 2 (JAK2) gene. In patients with 9pLOH, JAK2 had a homozygous GT transversion, causing phenylalanine to be substituted for valine at position 617 of JAK2 (V617F). All 51 patients with 9pLOH had the V617F mutation. Of 193 patients without 9pLOH, 66 were heterozygous for V617F and 127 did not have the mutation. The frequency of V617F was 65 percent among patients with polycythemia vera (83 of 128), 57 percent among patients with idiopathic myelofibrosis (13 of 23), and 23 percent among patients with essential thrombocythemia (21 of 93). V617F is a somatic mutation present in hematopoietic cells. Mitotic recombination probably causes both 9pLOH and the transition from heterozygosity to homozygosity for V617F. Genetic evidence and in vitro functional studies indicate that V617F gives hematopoietic precursors proliferative and survival advantages. Patients with the V617F mutation had a significantly longer duration of disease and a higher rate of complications (fibrosis, hemorrhage, and thrombosis) and treatment with cytoreductive therapy than patients with wild-type JAK2.

Conclusions A high proportion of patients with myeloproliferative disorders carry a dominant gain-of-function mutation of JAK2.

Source Information

From the Department of Research, Experimental Hematology (R.K., S.-S.T., R.T., R.C.S.), and the Departments of Hematology (A.S.B., J.R.P.) and Laboratory Medicine (A.T.), University Hospital Basel, Basel, Switzerland; and the Division of Hematology, University of Pavia Medical School and Istituto di Ricovero e Cura a Carattere Scientifico, Policlinico San Matteo, Pavia, Italy (F.P., M.C.).

Address reprint requests to Dr. Skoda at the Department of Research, University Hospital Basel, Hebelstr. 20, CH-4031 Basel, Switzerland, or at radek.skoda{at}unibas.ch.

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JAK2 Mutations in Myeloproliferative Disorders
Tefferi A., Lasho T. L., Gilliland G., Kralovics R., Cazzola M., Skoda R. C.
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N Engl J Med 2005; 353:1416-1417, Sep 29, 2005. Correspondence

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• Hexner, E. O., Serdikoff, C., Jan, M., Swider, C. R., Robinson, C., Yang, S., Angeles, T., Emerson, S. G., Carroll, M., Ruggeri, B., Dobrzanski, P. (2008). Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood 111: 5663-5671 [Abstract] [Full Text]  
• Velculescu, V. E. (2008). Defining the blueprint of the cancer genome. Carcinogenesis 29: 1087-1091 [Abstract] [Full Text]  
• Kiladjian, J.-J., Cervantes, F., Leebeek, F. W. G., Marzac, C., Cassinat, B., Chevret, S., Cazals-Hatem, D., Plessier, A., Garcia-Pagan, J.-C., Murad, S. D., Raffa, S., Janssen, H. L. A., Gardin, C., Cereja, S., Tonetti, C., Giraudier, S., Condat, B., Casadevall, N., Fenaux, P., Valla, D. C. (2008). The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases. Blood 111: 4922-4929 [Abstract] [Full Text]  
• Xing, S., Wanting, T. H., Zhao, W., Ma, J., Wang, S., Xu, X., Li, Q., Fu, X., Xu, M., Zhao, Z. J. (2008). Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice. Blood 111: 5109-5117 [Abstract] [Full Text]  
• Dusa, A., Staerk, J., Elliott, J., Pecquet, C., Poirel, H. A., Johnston, J. A., Constantinescu, S. N. (2008). Substitution of Pseudokinase Domain Residue Val-617 by Large Non-polar Amino Acids Causes Activation of JAK2. J. Biol. Chem. 283: 12941-12948 [Abstract] [Full Text]  
• Xiao, Z., Zhang, Y., Li, L., Nie, L., Yang, L., Xu, S. (2008). The Janus kinase 2 (JAK2) V617F mutation in Chinese patients with chronic myeloproliferative disorders. haematol 93: 787-788 [Full Text]  
• Lipka, D. B., Hoffmann, L. S., Heidel, F., Markova, B., Blum, M.-C., Breitenbuecher, F., Kasper, S., Kindler, T., Levine, R. L., Huber, C., Fischer, T. (2008). LS104, a non-ATP-competitive small-molecule inhibitor of JAK2, is potently inducing apoptosis in JAK2V617F-positive cells. Molecular Cancer Therapeutics 7: 1176-1184 [Abstract] [Full Text]  
• Xiang, Z., Zhao, Y., Mitaksov, V., Fremont, D. H., Kasai, Y., Molitoris, A., Ries, R. E., Miner, T. L., McLellan, M. D., DiPersio, J. F., Link, D. C., Payton, J. E., Graubert, T. A., Watson, M., Shannon, W., Heath, S. E., Nagarajan, R., Mardis, E. R., Wilson, R. K., Ley, T. J., Tomasson, M. H. (2008). Identification of somatic JAK1 mutations in patients with acute myeloid leukemia. Blood 111: 4809-4812 [Abstract] [Full Text]  
• Grebien, F., Kerenyi, M. A., Kovacic, B., Kolbe, T., Becker, V., Dolznig, H., Pfeffer, K., Klingmuller, U., Muller, M., Beug, H., Mullner, E. W., Moriggl, R. (2008). Stat5 activation enables erythropoiesis in the absence of EpoR and Jak2. Blood 111: 4511-4522 [Abstract] [Full Text]  
• Loriaux, M. M., Levine, R. L., Tyner, J. W., Frohling, S., Scholl, C., Stoffregen, E. P., Wernig, G., Erickson, H., Eide, C. A., Berger, R., Bernard, O. A., Griffin, J. D., Stone, R. M., Lee, B., Meyerson, M., Heinrich, M. C., Deininger, M. W., Gilliland, D. G., Druker, B. J. (2008). High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia. Blood 111: 4788-4796 [Abstract] [Full Text]  
• Tomasson, M. H., Xiang, Z., Walgren, R., Zhao, Y., Kasai, Y., Miner, T., Ries, R. E., Lubman, O., Fremont, D. H., McLellan, M. D., Payton, J. E., Westervelt, P., DiPersio, J. F., Link, D. C., Walter, M. J., Graubert, T. A., Watson, M., Baty, J., Heath, S., Shannon, W. D., Nagarajan, R., Bloomfield, C. D., Mardis, E. R., Wilson, R. K., Ley, T. J. (2008). Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia. Blood 111: 4797-4808 [Abstract] [Full Text]  
• Tiedt, R., Hao-Shen, H., Sobas, M. A., Looser, R., Dirnhofer, S., Schwaller, J., Skoda, R. C. (2008). Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood 111: 3931-3940 [Abstract] [Full Text]  
• Mannucci, P. M., Peyvandi, F. (2008). Thrombophilia Screening: Little Role for the JAK2V617F Mutation. Mayo Clin Proc. 83: 398-399 [Full Text]  
• Li, S., Kralovics, R., De Libero, G., Theocharides, A., Gisslinger, H., Skoda, R. C. (2008). Clonal heterogeneity in polycythemia vera patients with JAK2 exon12 and JAK2-V617F mutations. Blood 111: 3863-3866 [Abstract] [Full Text]  
• Wernig, G., Gonneville, J. R., Crowley, B. J., Rodrigues, M. S., Reddy, M. M., Hudon, H. E., Walz, C., Reiter, A., Podar, K., Royer, Y., Constantinescu, S. N., Tomasson, M. H., Griffin, J. D., Gilliland, D. G., Sattler, M. (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: 3751-3759 [Abstract] [Full Text]  
• Landolfi, R., Di Gennaro, L. (2008). Prevention of thrombosis in polycythemia vera and essential thrombocythemia. haematol 93: 331-335 [Full Text]  
• Lu, X., Huang, L. J.-S., Lodish, H. F. (2008). Dimerization by a Cytokine Receptor Is Necessary for Constitutive Activation of JAK2V617F. J. Biol. Chem. 283: 5258-5266 [Abstract] [Full Text]  
• Hama, A., Yagasaki, H., Takahashi, Y., Matsumoto, K., Kiyoi, H., Kojima, S. (2008). Response: Mutations of JAK2, JAK3 and GATA1 in acute megakaryoblastic leukemia of Down syndrome. Blood 111: 2493-2494 [Full Text]  
• Teofili, L., Foa, R., Giona, F., Larocca, L. M. (2008). Childhood polycythemia vera and essential thrombocythemia: does their pathogenesis overlap with that of adult patients?. haematol 93: 169-172 [Full Text]  
• Verstovsek, S., Manshouri, T., Quintas-Cardama, A., Harris, D., Cortes, J., Giles, F. J., Kantarjian, H., Priebe, W., Estrov, Z. (2008). WP1066, a Novel JAK2 Inhibitor, Suppresses Proliferation and Induces Apoptosis in Erythroid Human Cells Carrying the JAK2 V617F Mutation. Clin. Cancer Res. 14: 788-796 [Abstract] [Full Text]  
• Gondek, L. P., Tiu, R., O'Keefe, C. L., Sekeres, M. A., Theil, K. S., Maciejewski, J. P. (2008). Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS-derived AML. Blood 111: 1534-1542 [Abstract] [Full Text]  
• Pietra, D., Li, S., Brisci, A., Passamonti, F., Rumi, E., Theocharides, A., Ferrari, M., Gisslinger, H., Kralovics, R., Cremonesi, L., Skoda, R., Cazzola, M. (2008). Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders. Blood 111: 1686-1689 [Abstract] [Full Text]  
• Kawamata, N., Ogawa, S., Zimmermann, M., Kato, M., Sanada, M., Hemminki, K., Yamatomo, G., Nannya, Y., Koehler, R., Flohr, T., Miller, C. W., Harbott, J., Ludwig, W.-D., Stanulla, M., Schrappe, M., Bartram, C. R., Koeffler, H. P. (2008). Molecular allelokaryotyping of pediatric acute lymphoblastic leukemias by high-resolution single nucleotide polymorphism oligonucleotide genomic microarray. Blood 111: 776-784 [Abstract] [Full Text]  
• Kirsammer, G., Jilani, S., Liu, H., Davis, E., Gurbuxani, S., Le Beau, M. M., Crispino, J. D. (2008). Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome. Blood 111: 767-775 [Abstract] [Full Text]  
• Ruggeri, M., Rodeghiero, F., Tosetto, A., Castaman, G., Scognamiglio, F., Finazzi, G., Delaini, F., Mico, C., Vannucchi, A. M., Antonioli, E., De Stefano, V., Za, T., Gugliotta, L., Tieghi, A., Mazzucconi, M. G., Santoro, C., Barbui, T., for the Gruppo Italiano Malattie Ematologiche dell, (2008). Postsurgery outcomes in patients with polycythemia vera and essential thrombocythemia: a retrospective survey. Blood 111: 666-671 [Abstract] [Full Text]  
• Malcovati, L., Cazzola, M. (2008). Myelodysplastic/myeloproliferative disorders. haematol 93: 4-6 [Full Text]  
• Schmitt-Graeff, A. H., Teo, S.-S., Olschewski, M., Schaub, F., Haxelmans, S., Kirn, A., Reinecke, P., Germing, U., Skoda, R. C. (2008). JAK2V617F mutation status identifies subtypes of refractory anemia with ringed sideroblasts associated with marked thrombocytosis. haematol 93: 34-40 [Abstract] [Full Text]  
• Antonioli, E., Guglielmelli, P., Poli, G., Bogani, C., Pancrazzi, A., Longo, G., Ponziani, V., Tozzi, L., Pieri, L., Santini, V., Bosi, A., Vannucchi, A. M., for the Myeloproliferative Disorders Research Cons, (2008). Influence of JAK2V617F allele burden on phenotype in essential thrombocythemia. haematol 93: 41-48 [Abstract] [Full Text]  
• Sotlar, K., Bache, A., Stellmacher, F., Bultmann, B., Valent, P., Horny, H.-P. (2008). Systemic Mastocytosis Associated with Chronic Idiopathic Myelofibrosis: A Distinct Subtype of Systemic Mastocytosis-Associated Clonal Hematological Nonmast Cell Lineage Disorder Carrying the Activating Point Mutations KITD816V and JAK2V617F. J. Mol. Diagn. 10: 58-66 [Abstract] [Full Text]  
• Hellstrom-Lindberg, E., Cazzola, M. (2008). The Role of JAK2 Mutations in RARS and Other MDS. ASH Education Book 2008: 52-59 [Abstract] [Full Text]  
• James, C. (2008). The JAK2V617F Mutation in Polycythemia Vera and Other Myeloproliferative Disorders: One Mutation for Three Diseases?. ASH Education Book 2008: 69-75 [Abstract] [Full Text]