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

Jasmin Paris, Marcos Morgan, Joana Monteiro De Campos, Gary J. Spencer, Alena Shmakova, Ivayla Ivanova, Christopher Mapperley, Hannah Lawson, David Wotherspoon, Catarina Pires Sepulveda, Milica Vukovic, Lewis Allen, Annika Sarapuu, Andrea Tavosanis, Amelie Guitart, Arnaud Villacreces, Christian Much, Junho Choe, Ali Anvari Azar, Louie Van De LagemaatDouglas Vernimmen, Ali Nehme, Frederic Mazurier, Tim C. P. Somervaille, Richard I. Gregory, Donal O'Carroll, Kamil Kranc

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)137-148.E6
Number of pages12
JournalCell Stem Cell
Volume25
Issue number1
Early online date25 Apr 2019
DOIs
Publication statusPublished - 3 Jul 2019

Keywords

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

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