BLNK suppresses pre-B-cell leukemogenesis through inhibition of JAK3.
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.
Nakayama
Joji
J
Division of Molecular Biology, Research Institute for Biological Sciences, Tokyo University of Science, Noda, Japan.
Yamamoto
Mutsumi
M
Hayashi
Katsuhiko
K
Satoh
Hitoshi
H
Bundo
Kenji
K
Kubo
Masato
M
Goitsuka
Ryo
R
Farrar
Michael A
MA
Kitamura
Daisuke
D
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002453:Cell Cycle / Q000276:immunology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000276:immunology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D016193:G1 Phase / Q000276:immunology; D015973:Gene Expression Regulation, Leukemic; D015851:Interleukin-7 / Q000235:genetics / Q000378:metabolism; D053616:Janus Kinase 3 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology* / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; C493961:Cdkn1b protein, mouse; D015851:Interleukin-7; D050799:STAT5 Transcription Factor; C494096:Stat5b protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3