MEN1 mutations mediate clinical resistance to menin inhibition.

ABSTRACT: Chromatin-binding proteins are critical regulators of cell state in haematopoiesis^1,2. Acute leukaemias driven by rearrangement of the mixed lineage leukaemia 1 gene (KMT2Ar) or mutation of the nucleophosmin gene (NPM1) require the chromatin adapter protein menin, encoded by the MEN1 gene, to sustain aberrant leukaemogenic gene expression programs^3-5. In a phase 1 first-in-human clinical trial, the menin inhibitor revumenib, which is designed to disrupt the menin-MLL1 interaction, induced clinical responses in patients with leukaemia with KMT2Ar or mutated NPM1 (ref. ⁶). Here we identified somatic mutations in MEN1 at the revumenib-menin interface in patients with acquired resistance to menin inhibition. Consistent with the genetic data in patients, inhibit

SUBMITTER: Perner F 

PROVIDER: S-EPMC10157896 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature