title: Acquired expression ofCblQ367Pin mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia.
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 theCblgene, which encodes a negative regulator of cytokine signaling, in a subset of CMML patients. To investigate the contribution of mutantCblin CMML pathogenesis, we generated conditional knockin mice forCblthat express wild-typeCblin a steady state and inducibly expressCblQ367P, a CMML-associatedCblmutant.CblQ367Pmice 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 inCblQ367Phematopoietic stem cells, which promoted cell cycle progression and enhanced chemokine-chemokine receptor activity.Gem, a gene encoding a GTPase that is upregulated byCblQ367P, enhanced hematopoietic stem cell activity and induced myeloid cell proliferation. In addition,Evi1, a gene encoding a transcription factor, was found to cooperate withCblQ367Pand progress CMML to AML. Furthermore, targeted inhibition for the PI3K-AKT and JAK-STAT pathways efficiently suppressed the proliferative activity ofCblQ367P-bearing CMML cells. Our findings provide insights into the molecular mechanisms underlying mutantCbl-induced CMML and propose a possible molecular targeting therapy for mutantCbl-carrying CMML patients.
authors.affiliation: Department of Disease Model, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Nakata
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Kindai University, Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ueda
authors.affiliation: Department of Molecular Oncology, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Nagamachi
authors.affiliation: Department of Disease Model, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Norimasa
authors.initials: N
authors.lastname: Yamasaki
authors.affiliation: Department of Disease Model, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Ken-Ichiro
authors.initials: KI
authors.lastname: Ikeda
authors.affiliation: Department of Disease Model, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sera
authors.affiliation: Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Keiyo
authors.initials: K
authors.lastname: Takubo
authors.affiliation: Department of Molecular Oncology, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Kanai
authors.affiliation: Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Oda
authors.affiliation: Department of Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.affiliation: Department of Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Division of Cellular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Kohichiro
authors.initials: K
authors.lastname: Tsuji
authors.affiliation: Division of Cellular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ebihara
authors.affiliation: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Linda
authors.initials: L
authors.lastname: Wolff
authors.affiliation: Health Service Center, Ochanomizu University, Tokyo, Japan; and.
authors.forename: Zen-Ichiro
authors.initials: ZI
authors.lastname: Honda
authors.affiliation: Cancer Science Institute of Singapore, Center for Translational Medicine, National University of Singapore, Singapore.
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.affiliation: Department of Molecular Oncology, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Inaba
authors.affiliation: Department of Disease Model, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Honda
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002453:Cell Cycle; D015971:Gene Expression Regulation, Enzymologic; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D020559:Monomeric GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D020125:Mutation, Missense; D038042:Myelopoiesis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D050721:Proto-Oncogene Proteins c-cbl; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C088119:Gem protein, mouse; D020559:Monomeric GTP-Binding Proteins; C493849:Cbl protein, mouse