Targeting the RNA m6A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia

Jasmin Paris, Marcos Morgan, Joana Campos, Gary Spencer, Elena Shmakova, Ivayla Ivanova, Christopher Mapperley, Hannah Lawson, David Wotherspoon, Catarina Sepulveda, Milica Vukovic, Lewis Allen, Annika Sarapuu, Andrea Tavosanis, Arnaud Villacreces, Christian Much, Junho Choe, Ali Azar, Louie van de Lagemaat, Douglas VernimmenAli Nehme, Frederic Mazurier, Tim Somervaille, Richard Gregory, Donal O'Carroll, Kamil Kranc

Research output: Contribution to journalArticlepeer-review


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 the 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
Article numbere6
Pages (from-to)137-148
Number of pages12
JournalCell Stem Cell
Issue number1
Publication statusPublished - 3 Jul 2019

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre


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