Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 218, Issue 3, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20200829
Keywords
-
Categories
Funding
- Cancer Research UK program [C29967/A26787]
- Medical Research Council, Blood Cancer UK
- Barts Charity
- Kay Kendall Leukaemia Fund
- Wellcome Trust [108906/Z/15/Z, 106144]
- Wellcome Centre for Cell Biology [203149]
- European Cooperation in Science and Technology [EPITRAN CA16120]
- MRC [MR/L006340/1, MR/P010008/1, MC_PC_16082] Funding Source: UKRI
Ask authors/readers for more resources
The study reveals that YTHDF2 acts as a repressor of inflammatory pathways in hematopoietic stem cells, and long-term deletion of YTHDF2 results in HSC dysfunction and ultimately leads to multilineage hematopoiesis failure.
The mRNA N-6-methyladenosine (m(6)A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation of the m(6)A mRNA reader YTHDF2, which recognizes m(6)A-modified transcripts to promote m(6)A-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 m(6)A-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 m(6)A in long-term HSC maintenance.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available