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Blood, 19 March 2009, Vol. 113, No. 12, pp. 2746-2754. Prepublished online as a Blood First Edition Paper on January 12, 2009; DOI 10.1182/blood-2008-06-164368. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-06-164368v1 113/12/2746    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Cornejo, M. G. Articles by Mercher, T. Search for Related Content PubMed PubMed Citation Articles by Cornejo, M. G. Articles by Mercher, T. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Constitutive JAK3 activation induces lymphoproliferative syndromes in murine bone marrow transplantation models Melanie G. Cornejo1, Michael G. Kharas1, Miriam B. Werneck2, Séverine Le Bras3, Sandra A. Moore1, Brian Ball1, Marie Beylot-Barry4, Scott J. Rodig5, Jon C. Aster5, Benjamin H. Lee1, Harvey Cantor2, Jean-Philippe Merlio4, D. Gary Gilliland1,6, and Thomas Mercher1,7 1 Division of Hematology, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA; 2 Dana-Farber Cancer Institute, Boston, MA; 3 Children's Hospital, Boston, MA; 4 Pathology/Dermatology Department and EA2406, Centre Hospitalier Universitaire (CHU) de Bordeaux and Bordeaux 2 University, Bordeaux, France; 5 Department of Pathology, Brigham & Women's Hospital, Boston, MA; 6 Howard Hughes Medical Institute, Boston, MA; and 7 Inserm, E0210, Université Paris Descartes, Hôpital Necker, Paris, France The tyrosine kinase JAK3 plays a well-established role during normal lymphocyte development and is constitutively phosphorylated in several lymphoid malignancies. However, its contribution to lymphomagenesis remains elusive. In this study, we used the newly identified activating JAK3A572V mutation to elucidate the effect of constitutive JAK3 signaling on murine lymphopoiesis. In a bone marrow transplantation model, JAK3A572V induces an aggressive, fatal, and transplantable lymphoproliferative disorder characterized by the expansion of CD8+TCRβ+CD44+CD122+Ly-6C+ T cellsthat closely resemble an effector/memory T-cell subtype. Compared with wild-type counterparts, these cells show increased proliferative capacities in response to polyclonal stimulation, enhanced survival rates with elevated expression of Bcl-2, and increased production of interferon- (IFN) and tumor necrosis factor- (TNF), correlating with enhanced cytotoxic abilities against allogeneic target cells. Of interest, the JAK3A572V disease is epidermotropic and produces intraepidermal microabscesses. Taken together, these clinical features are reminiscent of those observed in an uncommon but aggressive subset of CD8+ human cutaneous T-cell lymphomas (CTCLs). However, we also observed a CD4+ CTCL-like phenotype when cells are transplanted in an MHC-I–deficient background. These data demonstrate that constitutive JAK3 activation disrupts T-cell homeostasis and induces lymphoproliferative diseases in mice. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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