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Blood, 15 October 2006, Vol. 108, No. 8, pp. 2770-2779. Prepublished online as a Blood First Edition Paper on June 27, 2006; DOI 10.1182/blood-2006-04-014712. This Article Full Text Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2006-04-014712v1 108/8/2770    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 Mercher, T. Articles by Gilliland, D. G. Search for Related Content PubMed PubMed Citation Articles by Mercher, T. Articles by Gilliland, D. G. Related Collections Hematopoiesis and Stem Cells Hemostasis, Thrombosis, and Vascular Biology Neoplasia Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA JAK2T875N is a novel activating mutation that results in myeloproliferative disease with features of megakaryoblastic leukemia in a murine bone marrow transplantation model Thomas Mercher, Gerlinde Wernig, Sandra A. Moore, Ross L. Levine, Ting-Lei Gu, Stefan Fröhling, Dana Cullen, Roberto D. Polakiewicz, Olivier A. Bernard, Titus J. Boggon, Benjamin H. Lee, and D. Gary Gilliland From the Division of Hematology, Department of Medicine, and the Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Cell Signalling Technology, Danvers, MA; the Institut National de la Santé et de la Recherche Médicale (INSERM) E0210, Université Paris V, Institut Fédératif de recherche Necker Enfants-Malades (IRNEM), Hôpital Necker, Paris, France; the Department of Pharmacology, Yale University School of Medicine, New Haven, CT; and the Howard Hughes Medical Institute, Chevy Chase, MD. Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia associated with a poor prognosis. However, there are relatively few insights into the genetic etiology of AMKL. We developed a screening assay for mutations that cause AMKL, based on the hypothesis that constitutive activation of STAT5 would be a biochemical indicator of mutation in an upstream effector tyrosine kinase. We screened human AMKL cell lines for constitutive STAT5 activation, and then used an approach combining mass spectrometry identification of tyrosine phosphorylated proteins and growth inhibition in the presence of selective small molecule tyrosine kinase inhibitors that would inform DNA sequence analysis of candidate tyrosine kinases. Using this strategy, we identified a new JAK2T875N mutation in the AMKL cell line CHRF-288-11. JAK2T875N is a constitutively activated tyrosine kinase that activates downstream effectors including STAT5 in hematopoietic cells in vitro. In a murine transplant model, JAK2T875N induced a myeloproliferative disease characterized by features of AMKL, including megakaryocytic hyperplasia in the spleen; impaired megakaryocyte polyploidization; and increased reticulin fibrosis of the bone marrow and spleen. These findings provide new insights into pathways and therapeutic targets that contribute to the pathogenesis of AMKL. 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