Acquired expression of CblQ367P in 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 the <i>Cbl</i> gene, which encodes a negative regulator of cytokine signaling, in a subset of CMML patients. To investigate the contribution of mutant <i>Cbl</i> in CMML pathogenesis, we generated conditional knockin mice for <i>Cbl</i> that express wild-type <i>Cbl</i> in a steady state and inducibly express <i>Cbl</i>^<i>Q367P</i> , a CMML-associated <i>Cbl</i> mutant. <i>Cbl</i>^<i>Q367P</i> 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 <i>Cbl</i>^<i>Q367P</i> hematopoietic stem cells, which promoted cell cycle progression and enhanced chemokine-chemokine receptor activity. <i>Gem</i>, a gene encoding a GTPase that is upregulated by <i>Cbl</i>^<i>Q367P</i> , enhanced hematopoietic stem cell activity and induced myeloid cell proliferation. In addition, <i>Evi1</i>, a gene encoding a transcription factor, was found to cooperate with <i>Cbl</i>^<i>Q367P</i> and progress CMML to AML. Furthermore, targeted inhibition for the PI3K-AKT and JAK-STAT pathways efficiently suppressed the proliferative activity of <i>Cbl</i>^<i>Q367P</i> -bearing CMML cells. Our findings provide insights into the molecular mechanisms underlying mutant <i>Cbl</i>-induced CMML and propose a possible molecular targeting therapy for mutant <i>Cbl</i>-carrying CMML patients.