{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T18:02:42Z","timestamp":1791396162073,"version":"4.3.3"},"reference-count":47,"publisher":"American Society of Hematology","issue":"7","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,2,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pre\u2013B-cell leukemia spontaneously develops in BLNK-deficient mice, and pre\u2013B-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\u2013B-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\u2212\/\u2212 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\u2013dependent proliferation and survival of pre\u2013B 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\u2013B-cell leukemia.<\/jats:p>","DOI":"10.1182\/blood-2008-07-166355","type":"journal-article","created":{"date-parts":[[2008,12,2]],"date-time":"2008-12-02T02:39:58Z","timestamp":1228185598000},"page":"1483-1492","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":105,"title":["BLNK suppresses pre\u2013B-cell leukemogenesis through inhibition of JAK3"],"prefix":"10.1182","volume":"113","author":[{"given":"Joji","family":"Nakayama","sequence":"first","affiliation":[{"name":"Division of Molecular Biology, Research Institute for Biological Sciences, Tokyo University of Science, Noda, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mutsumi","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Division of Molecular Biology, Research Institute for Biological Sciences, Tokyo University of Science, Noda, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuhiko","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Division of Molecular Biology, Research Institute for Biological Sciences, Tokyo University of Science, Noda, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Satoh","sequence":"additional","affiliation":[{"name":"Laboratory of Tumor Cell Biology, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Bundo","sequence":"additional","affiliation":[{"name":"Division of Molecular Biology, Research Institute for Biological Sciences, Tokyo University of Science, Noda, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Kubo","sequence":"additional","affiliation":[{"name":"Laboratory for Signal Network, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Kanagawa, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Goitsuka","sequence":"additional","affiliation":[{"name":"Division of Molecular Biology, Research Institute for Biological Sciences, Tokyo University of Science, Noda, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Farrar","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, Center for Immunology, The Cancer Center, University of Minnesota, Minneapolis; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Kitamura","sequence":"additional","affiliation":[{"name":"Division of Molecular Biology, Research Institute for Biological 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