Targeting SMC3 deacetylation synergizes with XPO1 inhibition to reprogram the epigenetic landscape and suppress NPM1-mutated acute myeloid leukemia

Acute myeloid leukemia (AML) is a prevalent hematologic malignancy. Mutations in Nucleophosmin (NPM1c) is the most frequent genetic alterations in AML. However, the epigenetic regulatory mechanisms of this AML subtype remain unclear. The cohesin complex, regulated by the acetyltransferase ESCO2, orchestrates chromatin organization and regulates gene expression. Here, we show that loss of ESCO2 promotes the progression of NPM1-mutated AML by destabilizing cohesin and the NuRD complex on chromatin, thereby enhancing the expression of genes associated with leukemia self-renewal capacity. Pharmacological HDAC8 inhibition restores SMC3 binding and induces differentiation and apoptosis in NPM1-mutated AML cells. Simultaneously targeting HDAC8 and nuclear exporter XPO1 reverses aberrant epigenetic landscape and represses self-renewal gene expression induced by ESCO2 deficiency. The combined treatment effectively eliminates NPM1-mutated AML cell lines and primary human AML cells in vitro and in vivo. This study reveals an ESCO2 deficiency-induced aberrant epigenetic landscape via SMC3 hypoacetylation and identifies a potential therapeutic strategy for NPM1-mutated AML. Epigenetic regulation in NPM1c-mutated acute myeloid leukemia (AML) is poorly understood. Here, the authors show that ESCO2 loss accelerates NPM1-mutated AML by disrupting cohesin and NuRD complexes on chromatin and thereby increasing the expression of genes linked to leukemia self-renewal.