Chronic myelomonocytic leukemia (CMML) is a heterogeneous hematologic malignancy with limited therapeutic options. Although RAS and RAS-modifying mutations (RASmut) are common and associated with poor prognosis, targeting RAS signaling has shown limited clinical success. Here, we define co-occurrence of RASmut and EZH2 inactivation (EZH2inact) as a distinct molecular subgroup of CMML characterized by aggressive disease biology. Mechanistically, RASmutEZH2inact drives selective MAPK/ERK hyperactivation in mature myeloid cells and hematopoietic stem and progenitor compartments. Transcriptomic analysis of a large independent myeloid neoplasm cohort (Beat-AML) further supports this finding, demonstrating selective activation of gene signatures of MAPK/ERK activation in RASmutEZH2inact cases. Functionally, this signaling activation promotes proliferation and myelomonocytic differentiation in human and murine models. Therapeutically, this MAPK/ERK upregulation confers increased sensitivity to MEK inhibition (MEKi). In a murine RasmutEzh2inact-driven CMML model, MEKi suppresses MAPK/ERK activity and reduces leukemic burden by impairing proliferation and myelomonocytic differentiation without inducing cell death. In primary human CMML samples ex vivo, MEKi shows stronger anti-proliferative effects in RASmutEZH2inact specimens compared with RASmut samples. Drug-sensitivity data from the Beat-AML cohort further supported this. Ultimately, these findings were confirmed in a patient-derived xenograft model, where MEKi reduced the leukemic burden by selectively inhibiting the proliferation of transplanted human RASmutEZH2inact leukemic cells. In summary, our data define RASmutEZH2inact CMML as a clinically relevant subgroup with selective MAPK/ERK hyperactivation and increased sensitivity to MEKi. They provide a mechanistic explanation for the limited efficacy of MEK inhibitors in unselected CMML and support molecularly guided use of MEK-targeted therapy in this patient population.
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