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Cell Stem Cell. 2019 Jul 3;25(1):137-148.e6. doi: 10.1016/j.stem.2019.03.021. Epub 2019 Apr 25.

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

Author information

1
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK; Laboratory of Haematopoietic Stem Cell & Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
2
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK; Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK; Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, UK.
3
Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4GJ, UK.
4
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
5
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK; Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK.
6
Laboratory of Haematopoietic Stem Cell & Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
7
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
8
Roslin Institute, University of Edinburgh, Edinburgh EH25 9RG, UK.
9
Université de Tours, CNRS, LNOx ERL 7001, Tours, France.
10
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK; Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK; Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, UK. Electronic address: donal.ocarroll@ed.ac.uk.
11
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK; Laboratory of Haematopoietic Stem Cell & Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK. Electronic address: kamil.kranc@qmul.ac.uk.

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 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.

KEYWORDS:

TNFR2; YTHDF2; acute myeloid leukemia; hematopoiesis; hematopoietic stem cell; leukemic stem cells; m(6)A modification; mRNA decay

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