Homoharringtonine suppresses acute myeloid leukemia progression by orchestrating EWSR1 phase separation in an m⁶A-YTHDF2-dependent mechanism.

ABSTRACT: Homoharringtonine (HHT) is widely used in combination regimens for acute myeloid leukemia (AML), yet its direct cellular targets remain undefined, limiting precision application. Here, we identified EWS RNA-binding protein 1 (EWSR1) as the primary target of HHT through chemical proteomics and biophysical validation. HHT bound the RNA recognition motif of EWSR1 with micromolar affinity, inducing an allosteric conformational switch that promoted oligomerization and liquid-liquid phase separation (LLPS). EWSR1 condensates selectively recruited the N⁶-methyladenosine (m⁶A) reader YTHDF2, forming cytoplasmic hubs where HHT disrupted YTHDF2-mRNA interactions. This sequestration attenuated m⁶A-mediated RNA decay, stabilizing key transcripts such as TNFRSF1B

SUBMITTER: Liu TT 

PROVIDER: S-EPMC12747546 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature