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Blood, 12 February 2009, Vol. 113, No. 7, pp. 1483-1492. Prepublished online as a Blood First Edition Paper on December 1, 2008; DOI 10.1182/blood-2008-07-166355. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-07-166355v1 113/7/1483    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 Nakayama, J. Articles by Kitamura, D. Search for Related Content PubMed PubMed Citation Articles by Nakayama, J. Articles by Kitamura, D. Related Collections Immunobiology Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA BLNK suppresses pre–B-cell leukemogenesis through inhibition of JAK3 Joji Nakayama1, Mutsumi Yamamoto1, Katsuhiko Hayashi1, Hitoshi Satoh2, Kenji Bundo1, Masato Kubo3, Ryo Goitsuka1, Michael A. Farrar4, and Daisuke Kitamura1,5 1 Division of Molecular Biology, Research Institute for Biological Sciences, Tokyo University of Science, Noda, Japan; 2 Laboratory of Tumor Cell Biology, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan; 3 Laboratory for Signal Network, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Kanagawa, Japan; 4 Department of Laboratory Medicine and Pathology, Center for Immunology, The Cancer Center, University of Minnesota, Minneapolis; and 5 Faculty of Pharmaceutical Science, Tokyo University of Science, Noda, Japan Pre–B-cell leukemia spontaneously develops in BLNK-deficient mice, and pre–B-cell acute lymphoblastic leukemia cells in children often lack BLNK protein expression, demonstrating that BLNK functions as a tumor suppressor. However, the mechanism by which BLNK suppresses pre–B-cell leukemia, as well as the identification of other genetic alterations that collaborate with BLNK deficiency to cause leukemogenesis, are still unknown. Here, we demonstrate that the JAK3/STAT5 signaling pathway is constitutively activated in pre-B leukemia cells derived from BLNK–/– mice, mostly due to autocrine production of IL-7. Inhibition of IL-7R signaling or JAK3/STAT5 activity resulted in the induction of p27kip1 expression and cell-cycle arrest, accompanied by apoptosis in the leukemia cells. Transgene-derived constitutively active STAT5 (STAT5b-CA) strongly synergized with the loss of BLNK to initiate leukemia in vivo. In the leukemia cells, exogenously expressed BLNK inhibited autocrine JAK3/STAT5 signaling, resulting in p27kip1 induction, cell-cycle arrest, and apoptosis. BLNK-inhibition of JAK3 was dependent on the binding of BLNK to JAK3. These data indicate that BLNK normally regulates IL-7–dependent proliferation and survival of pre–B cells through direct inhibition of JAK3. Thus, somatic loss of BLNK and concomitant mutations leading to constitutive activation of Jak/STAT5 pathway result in the generation of pre–B-cell leukemia. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Trageser, I. Iacobucci, R. Nahar, C. Duy, G. von Levetzow, L. Klemm, E. Park, W. Schuh, T. Gruber, S. Herzog, et al. Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function J. Exp. Med., August 3, 2009; 206(8): 1739 - 1753. [Abstract] [Full Text] [PDF]

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