N6-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation

N6-Methyladenosine (m6A) on mRNAs mediates different biological processes and its dysregulation contributes to tumorigenesis. How m6A dictates its diverse molecular and cellular effects in leukemias remains unknown. We found that YTHDC1 is the essential m6A reader in myeloid leukemia from a genome-wide CRISPR screen and that m6A is required for YTHDC1 to undergo liquid-liquid phase separation and form nuclear YTHDC1-m6A condensates (nYACs). The number of nYACs increases in acute myeloid leukemia (AML) cells compared with normal hematopoietic stem and progenitor cells. AML cells require the nYACs to maintain cell survival and the undifferentiated state that is critical for leukemia maintenance. Furthermore, nYACs enable YTHDC1 to protect m6A-mRNAs from the PAXT complex and exosome-associated RNA degradation. Collectively, m6A is required for the formation of a nuclear body mediated by phase separation that maintains mRNA stability and control cancer cell survival and differentiation. [Display omitted] •YTHDC1 is required for AML cell survival, differentiation state, and leukemogenesis•YTHDC1 binds to m6A and forms nuclear condensates (nYACs) mediated by LLPS•nYACs are more abundant in AML cells compared with normal blood cells•nYACs protect mRNAs (i.e., MYC and others) from degradation by the PAXT complex Using AML cell lines and patient samples Cheng et al. identify a requirement for YTHDC1 in myeloid leukemogenesis. YTHDC1 undergoes liquid-liquid phase separation by binding to m6A to form dynamic nuclear condensates. These nuclear bodies are increased in myeloid leukemia cells and protect mRNAs from the PAXT-exosome complex.