Acquired expression of CblQ367P in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia

• Published in: Blood 2017-04, Vol.129 (15), p.2148-2160
• Main Authors: Nakata, Yuichiro, Ueda, Takeshi, Nagamachi, Akiko, Yamasaki, Norimasa, Ikeda, Ken-ichiro, Sera, Yasuyuki, Takubo, Keiyo, Kanai, Akinori, Oda, Hideaki, Sanada, Masashi, Ogawa, Seishi, Tsuji, Kohichiro, Ebihara, Yasuhiro, Wolff, Linda, Honda, Zen-ichiro, Suda, Toshio, Inaba, Toshiya, Honda, Hiroaki
• Format: Article
• Language: English
• Subjects: Myeloid Neoplasia
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2016-06-724658

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 CblQ367P, a CMML-associated Cbl mutant. CblQ367P 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 CblQ367P hematopoietic stem cells, which promoted cell cycle progression and enhanced chemokine-chemokine receptor activity. Gem, a gene encoding a GTPase that is upregulated by CblQ367P, enhanced hematopoietic stem cell activity and induced myeloid cell proliferation. In addition, Evi1, a gene encoding a transcription factor, was found to cooperate with CblQ367P and progress CMML to AML. Furthermore, targeted inhibition for the PI3K-AKT and JAK-STAT pathways efficiently suppressed the proliferative activity of CblQ367P-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. •Acquired expression of CblQ367P induces sustained proliferation of myelomonocytes, multilineage dysplasia, and splenomegaly resembling CMML.•Combined inhibition of PI3K and JAK2 efficiently suppressed the growth of CblQ367P-induced CMML cells.