RRC ID 47689
Author Nakata Y, Ueda T, Nagamachi A, Yamasaki N, Ikeda KI, Sera Y, Takubo K, Kanai A, Oda H, Sanada M, Ogawa S, Tsuji K, Ebihara Y, Wolff L, Honda ZI, Suda T, Inaba T, Honda H.
Title Acquired expression of CblQ367P in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia.
Journal Blood
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.
Volume 129(15)
Pages 2148-2160
Published 2017-4-13
DOI 10.1182/blood-2016-06-724658
PII S0006-4971(20)33492-3
PMID 28209720
PMC PMC5391621
MeSH Amino Acid Substitution Animals Cell Cycle* Gene Expression Regulation, Enzymologic Hematopoietic Stem Cells* / metabolism Hematopoietic Stem Cells* / pathology Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / genetics Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / metabolism Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / pathology Leukemia, Myeloid, Acute / genetics Leukemia, Myeloid, Acute / metabolism Leukemia, Myeloid, Acute / pathology Mice Mice, Transgenic Monocytes / metabolism Monocytes / pathology Monomeric GTP-Binding Proteins / biosynthesis Monomeric GTP-Binding Proteins / genetics Mutation, Missense* Myelopoiesis* Phosphatidylinositol 3-Kinases / genetics Phosphatidylinositol 3-Kinases / metabolism Proto-Oncogene Proteins c-akt / genetics Proto-Oncogene Proteins c-akt / metabolism Proto-Oncogene Proteins c-cbl* / biosynthesis Proto-Oncogene Proteins c-cbl* / genetics Signal Transduction Up-Regulation*
IF 17.794
Times Cited 5
Mice RBRC01834