The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function

  • J Exp Med. 2021 Mar 1;218(3):e20200829. doi: 10.1084/jem.20200829.
Christopher Mapperley  1  2 ,  Louie N van de Lagemaat  1  2 ,  Hannah Lawson  2 ,  Andrea Tavosanis  2 ,  Jasmin Paris  1  2 ,  Joana Campos  2 ,  David Wotherspoon  2 ,  Jozef Durko  2 ,  Annika Sarapuu  2 ,  Junho Choe  3  4 ,  Ivayla Ivanova  1  5 ,  Daniela S Krause  6 ,  Alex von Kriegsheim  7 ,  Christian Much  1  5 ,  Marcos Morgan  1  5 ,  Richard I Gregory  3  4 ,  Adam J Mead  8 ,  Dónal O'Carroll  1  5  9 ,  Kamil R Kranc  1  2
Affiliations
  • 1. Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
  • 2. Laboratory of Haematopoietic Stem Cell and Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
  • 3. Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA.
  • 4. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA.
  • 5. Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.
  • 6. Georg-Speyer-Haus and Goethe University, Frankfurt, Germany.
  • 7. Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, Edinburgh, UK.
  • 8. Medical Research Council Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, UK.
  • 9. Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.
PMID: 33156926 DOI: 10.1084/jem.20200829
Abstract

The mRNA N6-methyladenosine (m6A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation of the m6A mRNA reader YTHDF2, which recognizes m6A-modified transcripts to promote m6A-mRNA degradation, results in hematopoietic stem cell (HSC) expansion and compromises Acute Myeloid Leukemia. Here we investigate the long-term impact of YTHDF2 deletion on HSC maintenance and multilineage hematopoiesis. We demonstrate that Ythdf2-deficient HSCs from young mice fail upon serial transplantation, display increased abundance of multiple m6A-modified inflammation-related transcripts, and chronically activate proinflammatory pathways. Consistent with the detrimental consequences of chronic activation of inflammatory pathways in HSCs, hematopoiesis-specific YTHDF2 deficiency results in a progressive myeloid bias, loss of lymphoid potential, HSC expansion, and failure of aged Ythdf2-deficient HSCs to reconstitute multilineage hematopoiesis. Experimentally induced inflammation increases YTHDF2 expression, and YTHDF2 is required to protect HSCs from this insult. Thus, our study positions YTHDF2 as a repressor of inflammatory pathways in HSCs and highlights the significance of m6A in long-term HSC maintenance.