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Targeting the RNA m6A reader YTHDF2 selectively compromises cancer stem cells in acute myeloid leukemia

Research output: Contribution to journalArticle

  • Gary Spencer
  • Christopher Mapperley
  • Hannah Lawson
  • David Wotherspoon
  • Annika Sarapuu
  • Andrea Tavosanis
  • Christian Much
  • Choe Junho
  • Ali Nehme
  • Frederic Mazurier
  • Tim Somervaille
  • Richard Gregory

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Original languageEnglish
Number of pages12
JournalCell Stem Cell
Early online date25 Apr 2019
Publication statusPublished - 3 Jul 2019


Acute myeloid leukemia (AML) is an aggressive clonal disorder of hematopoietic stem cells (HSCs) and primitive progenitors that blocks their myeloid differentiation generating self-renewing leukemic stem cells (LSCs). Here we show that the mRNA m6A reader YTHDF2 is overexpressed in a broad spectrum of human AML and is required for disease initiation, as well as propagation in mouse and human AML.

YTHDF2 decreases the half-life of diverse m6A transcripts that contribute to the overall integrity of LSC function, including tumor necrosis factor receptor Tnfrsf2 whose upregulation in Ythdf2-deficient LSCs primes cells for apoptosis. Intriguingly, YTHDF2 is not essential for normal HSC function with YTHDF2-deficiency actually enhancing HSC activity. Thus, we identify YTHDF2 as a unique therapeutic target whose inhibition selectively targets LSCs while promoting HSC expansion.

    Research areas

  • m6A modification, mRNA decay, acute myeloid leukemia, Leukemic stem cells, hematopoietic stem cells

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