Targeting the RNA m(6)A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia

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 m(6)A reader YTHDF2 is overexpressed in a broad spect...

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Detalles Bibliográficos
Autores principales: 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, Dónal, Kranc, Kamil R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2019
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617387/
https://www.ncbi.nlm.nih.gov/pubmed/31031138
http://dx.doi.org/10.1016/j.stem.2019.03.021
Descripción
Sumario: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 m(6)A 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 m(6)A 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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