Targeting the RNA m6A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemiaopen access
- Authors
- Paris, Jasmin; Morgan, Marcos; Campos, Joana; Spencer, Gary J.; Shmakova, Alena; Ivanova, Ivayla; Mapperley, Christopher; Lawson, Hannah; Wotherspoon, David A.; Sepulveda, Catarina; Vukovic, Milica; Allen, Lewis; Sarapuu, Annika; Tavosanis, Andrea; Guitart, Amelie V.; Villacreces, Arnaud; Much, Christian; Choe, Junho; Azar, Ali; van de Lagemaat, Louie N.; Vernimmen, Douglas; Nehme, Ali; Mazurier, Frederic; Somervaille, Tim C. P.; Gregory, Richard I.; O'Carroll, Donal; Kranc, Kamil R.
- Issue Date
- Jul-2019
- Publisher
- CELL PRESS
- Keywords
- acute myeloid leukemia; hematopoiesis; hematopoietic stem cell; leukemic stem cells; m6A modification; mRNA decay; TNFR2; YTHDF2
- Citation
- CELL STEM CELL, v.25, no.1, pp.137 - 148
- Indexed
- SCIE
SCOPUS
- Journal Title
- CELL STEM CELL
- Volume
- 25
- Number
- 1
- Start Page
- 137
- End Page
- 148
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/147406
- DOI
- 10.1016/j.stem.2019.03.021
- ISSN
- 1934-5909
- 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.
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