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

Yuanming Cheng, Wei Xie, Brian F. Pickering, Karen L. Chu, Angela M. Savino, Xuejing Yang, Hanzhi Luo, Diu Tt Nguyen, Shanlan Mo, Ersilia Barin, Anthony Velleca, Thomas M. Rohwetter, Dinshaw J. Patel, Samie R. Jaffrey, Michael G. Kharas

Research output: Contribution to journalArticlepeer-review

156 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)958-972.e8
Number of pages23
JournalCancer Cell
Volume39
Issue number7
DOIs
StatePublished - Jul 12 2021
Externally publishedYes

Keywords

  • RNA methylation
  • RNA-binding proteins
  • differentiation
  • myeloid leukemia
  • phase separation
  • Cell Proliferation
  • Humans
  • Phase Transition
  • DNA Methylation
  • RNA, Messenger/chemistry
  • Hematopoiesis
  • Cell Nucleus/genetics
  • Female
  • Cell Differentiation
  • Tumor Cells, Cultured
  • RNA Splicing Factors/genetics
  • Mice, SCID
  • RNA Stability
  • Xenograft Model Antitumor Assays
  • Adenosine/analogs & derivatives
  • Animals
  • Nerve Tissue Proteins/genetics
  • Mice, Inbred NOD
  • Proto-Oncogene Proteins c-myc/genetics
  • Mice
  • Liquid-Liquid Extraction
  • Leukemia, Myeloid, Acute/genetics
  • Apoptosis

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