1. Acquired expression of CblQ367P in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia
- Author
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Zen-ichiro Honda, Takeshi Ueda, Toshio Suda, Akinori Kanai, Kenichiro Ikeda, Keiyo Takubo, Hideaki Oda, Seishi Ogawa, Toshiya Inaba, Yasuhiro Ebihara, Yasuyuki Sera, Yuichiro Nakata, Kohichiro Tsuji, Masashi Sanada, Akiko Nagamachi, Linda Wolff, Hiroaki Honda, and Norimasa Yamasaki
- Subjects
0301 basic medicine ,Myeloid ,Immunology ,Mutation, Missense ,Chronic myelomonocytic leukemia ,Mice, Transgenic ,Biology ,Biochemistry ,Gene Expression Regulation, Enzymologic ,Monocytes ,Mice ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,0302 clinical medicine ,Inside BLOOD Commentary ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Proto-Oncogene Proteins c-cbl ,PI3K/AKT/mTOR pathway ,Monomeric GTP-Binding Proteins ,Myelopoiesis ,Myeloid Neoplasia ,Cell Cycle ,Myeloid leukemia ,Hematopoietic stem cell ,Cell Biology ,Hematology ,Hematopoietic Stem Cells ,medicine.disease ,Molecular biology ,Up-Regulation ,Leukemia, Myeloid, Acute ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,Amino Acid Substitution ,030220 oncology & carcinogenesis ,Mutation ,Stem cell ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
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.
- Published
- 2017
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