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Blood, 1 June 2007, Vol. 109, No. 11, pp. 4924-4929. Prepublished online as a Blood First Edition Paper on February 22, 2007; DOI 10.1182/blood-2006-08-039735. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2006-08-039735v1 109/11/4924    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hookham, M. B. Articles by Johnston, J. A. Search for Related Content PubMed PubMed Citation Articles by Hookham, M. B. Articles by Johnston, J. A. Related Collections Hematopoiesis and Stem Cells Neoplasia Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA The myeloproliferative disorder–associated JAK2 V617F mutant escapes negative regulation by suppressor of cytokine signaling 3 Michelle B. Hookham1, Joanne Elliott1, Yvonne Suessmuth1, Judith Staerk2,3, Alister C. Ward4, William Vainchenker6, Melanie J. Percy5, Mary Frances McMullin5, Stefan N. Constantinescu2,3, and James A. Johnston1 1 Infection and Immunity Group, Centre for Cancer Research and Cell Biology, Queens University, Belfast, United Kingdom; 2 Ludwig Institute for Cancer Research, Brussels, Belgium; 3 Christian de Duve Institute for Cellular Pathology, Université Catholique de Louvain, Brussels, Belgium; 4 School of Life and Environmental Science, Deakin University, Burwood, Australia; 5 Haematology, Belfast City Hospital, United Kingdom; and 6 Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U) 790, Institut Gustave Roussy, Villejuif, France The somatic JAK2 valine-to-phenylalanine (V617F) mutation has been detected in up to 90% of patients with polycythemia and in a sizeable proportion of patients with other myeloproliferative disorders such as essential thrombocythemia and idiopathic myelofibrosis. Suppressor of cytokine signaling 3 (SOCS3) is known to be a strong negative regulator of erythropoietin (EPO) signaling through interaction with both the EPO receptor (EPOR) and JAK2. We report here that JAK2 V617F cannot be regulated and that its activation is actually potentiated in the presence of SOCS3. Instead of acting as a suppressor, SOCS3 enhanced the proliferation of cells expressing both JAK2 V617F and EPOR. Additionally, although SOCS1 and SOCS2 are degraded in the presence of JAK2 V617F, turnover of SOCS3 is inhibited by the JAK2 mutant kinase and this correlated with marked tyrosine phosphorylation of SOCS3 protein. We also observed constitutive tyrosine phosphorylation of SOCS3 in peripheral blood mononuclear cells (PBMCs) derived from patients homozygous for the JAK2 V617F mutant. These findings suggest that the JAK2 V617F has overcome normal SOCS regulation by hyperphosphorylating SOCS3, rendering it unable to inhibit the mutant kinase. Thus, JAK2 V617F may even exploit SOCS3 to potentiate its myeloproliferative capacity. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Gery, Q. Cao, S. Gueller, H. Xing, A. Tefferi, and H. P. Koeffler Lnk inhibits myeloproliferative disorder-associated JAK2 mutant, JAK2V617F J. Leukoc. Biol., June 1, 2009; 85(6): 957 - 965. [Abstract] [Full Text] [PDF] J. Elliott, Y. Suessmuth, L. M. Scott, K. Nahlik, M. F. McMullin, S. N. Constantinescu, A. R. Green, and J. A. Johnston SOCS3 tyrosine phosphorylation as a potential bio-marker for myeloproliferative neoplasms associated with mutant JAK2 kinases Haematologica, April 1, 2009; 94(4): 576 - 580. [Abstract] [Full Text] [PDF] N. Fourouclas, J. Li, D. C. Gilby, P. J. Campbell, P. A. Beer, E. M. Boyd, A. C. Goodeve, D. Bareford, C. N. Harrison, J. T. Reilly, et al. 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Interv., February 1, 2008; 8(1): 19 - 21. [Abstract] [Full Text] [PDF] J.-L. Chen, A. Limnander, and P. B. Rothman Pim-1 and Pim-2 kinases are required for efficient pre-B-cell transformation by v-Abl oncogene Blood, February 1, 2008; 111(3): 1677 - 1685. [Abstract] [Full Text] [PDF] C. James The JAK2V617F Mutation in Polycythemia Vera and Other Myeloproliferative Disorders: One Mutation for Three Diseases? Hematology, January 1, 2008; 2008(1): 69 - 75. [Abstract] [Full Text] [PDF] S. Gery, S. Gueller, K. Chumakova, N. Kawamata, L. Liu, and H. P. Koeffler Adaptor protein Lnk negatively regulates the mutant MPL, MPLW515L associated with myeloproliferative disorders Blood, November 1, 2007; 110(9): 3360 - 3364. [Abstract] [Full Text] [PDF] R. Skoda The Genetic Basis of Myeloproliferative Disorders Hematology, January 1, 2007; 2007(1): 1 - 10. [Abstract] [Full Text] [PDF]

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