論文

査読有り
2017年4月

Acquired expression of Cbl(Q367P) in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia

BLOOD
  • Yuichiro Nakata
  • ,
  • Takeshi Ueda
  • ,
  • Akiko Nagamachi
  • ,
  • Norimasa Yamasaki
  • ,
  • Ken-ichiro Ikeda
  • ,
  • Yasuyuki Sera
  • ,
  • Keiyo Takubo
  • ,
  • Akinori Kanai
  • ,
  • Hideaki Oda
  • ,
  • Masashi Sanada
  • ,
  • Seishi Ogawa
  • ,
  • Kohichiro Tsuji
  • ,
  • Yasuhiro Ebihara
  • ,
  • Linda Wolff
  • ,
  • Zen-ichiro Honda
  • ,
  • Toshio Suda
  • ,
  • Toshiya Inaba
  • ,
  • Hiroaki Honda

129
15
開始ページ
2148
終了ページ
2160
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1182/blood-2016-06-724658
出版者・発行元
AMER SOC HEMATOLOGY

Chronic myelomonocytic leukemia (CMML) is a hematological malignancy characterized by uncontrolled proliferation of dysplastic myelomonocytes and frequent progression to acute myeloid leukemia (AML). We identified mutations in the Cbl gene, which encodes a negative regulator of cytokine signaling, in a subset of CMML patients. To investigate the contribution of mutant Cbl in CMML pathogenesis, we generated conditional knockin mice for Cbl that express wild-type Cbl in a steady state and inducibly express Cbl(Q367P), a CMML-associated Cbl mutant. Cbl(Q367P) mice exhibited sustained proliferation of myelomonocytes, multilineage dysplasia, and splenomegaly, which are the hallmarks of CMML. The phosphatidylinositol 3-kinase (PI3K)-AKT and JAK-STAT pathways were constitutively activated in Cbl(Q367P) hematopoietic stem cells, which promoted cell cycle progression and enhanced chemokine-chemokine receptor activity. Gem, a gene encoding a GTPase that is upregulated by Cbl(Q367P), enhanced hematopoietic stem cell activity and induced myeloid cell proliferation. In addition, Evi1, a gene encoding a transcription factor, was found to cooperate with Cbl(Q367P) and progress CMML to AML. Furthermore, targeted inhibition for the PI3K-AKT and JAK-STAT pathways efficiently suppressed the proliferative activity of Cbl(Q367P) -bearing CMML cells. Our findings provide insights into the molecular mechanisms underlying mutant Cbl-induced CMML and propose a possible molecular targeting therapy for mutant Cbl-carrying CMML patients.

Web of Science ® 被引用回数 : 13

リンク情報
DOI
https://doi.org/10.1182/blood-2016-06-724658
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000399008200020&DestApp=WOS_CPL
ID情報
  • DOI : 10.1182/blood-2016-06-724658
  • ISSN : 0006-4971
  • eISSN : 1528-0020
  • Web of Science ID : WOS:000399008200020

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