Work

Dual targeting of EZH2 and EZH1 drives exit of leukemia stem cells from quiescence and potentiates chemotherapy in acute myeloid leukemia

Year: 2025

Type: article

Abstract: Despite recent therapeutic advances, overall survival of acute myeloid leukemia (AML) patients remains poor. Cytarabine (Ara-C), in combination with anthracyclines, induces complete remissions in 60–80% of AML patients, with only a fraction of them achieving long-term survival, and 60–90% of refractory AML patients succumb to the disease. Treatment failure is mainly attributed to the insufficient eradication of cell-kinetically quiescent leukemia stem/progenitor cells (LSPCs) that reside in the bone marrow (BM) niche. Therefore, overcoming the dormancy of LSPCs should improve survival of AML patients [ 1 ]. Quiescent LSPCs are dependent on enhancer of zeste homolog (EZH)2 and EZH1, the key catalytic subunits of the polycomb repressive complex 2 (PRC2). Genetic ablation of EZH2/1 in an AML model depleted quiescent LSPCs [ 2 ]. In this study, we observed that inhibition of EZH2/1 by valemetostat tosylate (DS-3201b or valemetostat) monotherapy in a phase 1 clinical trial induced proliferation and mobilization of immature blasts into circulation in AML patients. Preclinical experiments in vitro and in vivo recapitulated the findings and indicated the therapeutic potential of valemetostat in combination with Ara-C.

Source: Blood Cancer Journal

DOI: 10.1038/s41408-025-01266-0