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

N-Methyladenosine (mA) on mRNAs mediates different biological processes and its dysregulation contributes to tumorigenesis. How mA dictates its diverse molecular and cellular effects in leukemias remains unknown. We found that YTHDC1 is the essential mA reader in myeloid leukemia from a genome-wide CRISPR screen and that mA is required for YTHDC1 to undergo liquid-liquid phase separation and form nuclear YTHDC1-mA 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 mA-mRNAs from the PAXT complex and exosome-associated RNA degradation. Collectively, mA is required for the formation of a nuclear body mediated by phase separation that maintains mRNA stability and control cancer cell survival and differentiation.