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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.

Original publication

DOI

10.1084/jem.20200829

Type

Journal article

Journal

J Exp Med

Publication Date

01/03/2021

Volume

218

Keywords

Adenosine, Animals, Cell Lineage, Cell Proliferation, Cellular Senescence, Gene Deletion, Hematopoiesis, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Inflammation, Lymphocytes, Mice, Inbred C57BL, Myeloid Cells, RNA, Messenger, RNA-Binding Proteins, Mice