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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3751-3759. Prepublished online as a Blood First Edition Paper on January 23, 2008; DOI 10.1182/blood-2007-07-102186. This Article Full Text (PDF) All Versions of this Article: blood-2007-07-102186v1 111/7/3751    most recent Alert me when this article is cited Alert me if a correction is posted 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 Wernig, G. Articles by Sattler, M. Search for Related Content PubMed PubMed Citation Articles by Wernig, G. Articles by Sattler, M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 19, 2007 Accepted January 16, 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 Gerlinde Wernig, Jeffrey R Gonneville, Brian J Crowley, Margret S Rodrigues, Mamatha M Reddy, Heidi E Hudon, Christoph Walz, Andreas Reiter, Klaus Podar, Yohan Royer, Stefan N Constantinescu, Michael H Tomasson, James D Griffin, D Gary Gilliland, and Martin Sattler* Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States III. Medizinische Universitatsklinik, Fakultat fur Klinische Medizin Mannheim der Universitat Heidelberg, Mannheim, Germany Signal Transduction Group, Ludwig Institute for Cancer Research, Brussels, Belgium Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States * Corresponding author; email: martin_sattler{at}dfci.harvard.edu. The V617F activating point mutation in Jak2 is associated with a proportion of myeloproliferative disorders. In normal hematopoietic cells, Jak2 signals only when associated with a growth factor receptor, such as the erythropoietin receptor (EpoR). We sought to identify the molecular requirements for activation of Jak2V617F by introducing a point mutation in the FERM domain (Y114A), required for receptor binding. Whereas BaF3.EpoR cells are readily transformed by Jak2V617F to Epo-independence, we found that the addition of the FERM domain mutation blocked transformation and the induction of reactive oxygen species. Further, while cells expressing Jak2V617F had constitutive activation of STAT5, cells expressing Jak2 V617F/Y114A did not, suggesting that signaling is defective at a very proximal level. In addition, expression of the Myc and Pim proto-oncogenes by Jak2V617F was found to be FERM domain-dependent. An inducible constitutively active STAT5 mutant expressed in BaF3 cells was sufficient to induce Myc and Pim. Finally, the FERM domain in Jak2V617F was also required for abnormal hematopoiesis in transduced primary murine fetal liver cells. Overall, our results suggest that constitutive activation of Jak2 requires an intact FERM domain for a transforming phenotype, and is necessary for activation of the major target of Jak2, STAT5. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. S. Fernandes, M. M. Reddy, J. R. Gonneville, S. C. DeRoo, K. Podar, J. D. Griffin, D. M. Weinstock, and M. Sattler BCR-ABL promotes the frequency of mutagenic single-strand annealing DNA repair Blood, August 27, 2009; 114(9): 1813 - 1819. [Abstract] [Full Text] [PDF] T. R. Hercus, D. Thomas, M. A. Guthridge, P. G. Ekert, J. King-Scott, M. W. Parker, and A. F. Lopez The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease Blood, August 13, 2009; 114(7): 1289 - 1298. [Abstract] [Full Text] [PDF] 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] T. Hornakova, J. Staerk, Y. Royer, E. Flex, M. Tartaglia, S. N. Constantinescu, L. Knoops, and J.-C. Renauld Acute Lymphoblastic Leukemia-associated JAK1 Mutants Activate the Janus Kinase/STAT Pathway via Interleukin-9 Receptor {alpha} Homodimers J. Biol. Chem., March 13, 2009; 284(11): 6773 - 6781. [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]

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