BLNK suppresses pre B-cell leukemogenesis through inhibition of JAK3

Joji Nakayama, Mutsumi Yamamoto, Katsuhiko Hayashi, Hitoshi Satoh, Kenji Bundo, Masato Kubo, Ryo Goitsuka, Michael A. Farrar, Daisuke Kitamura

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83 Scopus citations

Abstract

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 p27 kip1 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 p27 kip1 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.

Original languageEnglish (US)
Pages (from-to)1483-1492
Number of pages10
JournalBlood
Volume113
Issue number7
DOIs
StatePublished - Feb 12 2009

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    Nakayama, J., Yamamoto, M., Hayashi, K., Satoh, H., Bundo, K., Kubo, M., Goitsuka, R., Farrar, M. A., & Kitamura, D. (2009). BLNK suppresses pre B-cell leukemogenesis through inhibition of JAK3. Blood, 113(7), 1483-1492. https://doi.org/10.1182/blood-2008-07-166355