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

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