N6-Methyladenosine (m6A) on mRNAs mediates different biological processes and its dysregulation contributes to tumorigenesis. How m6A dictates its diverse molecular and cellular effects in leukemias remains unknown. We found that YTHDC1 is the essential m6A reader in myeloid leukemia from a genome-wide CRISPR screen and that m6A is required for YTHDC1 to undergo liquid-liquid phase separation and form nuclear YTHDC1-m6A condensates (nYACs). The number of nYACs increases in acute myeloid leukemia (AML) cells compared with normal hematopoietic stem and progenitor cells. AML cells require the nYACs to maintain cell survival and the undifferentiated state that is critical for leukemia maintenance. Furthermore, nYACs enable YTHDC1 to protect m6A-mRNAs from the PAXT complex and exosome-associated RNA degradation. Collectively, m6A is required for the formation of a nuclear body mediated by phase separation that maintains mRNA stability and control cancer cell survival and differentiation.

Cheng, Y., Xie, W., Pickering, B., Chu, K., Savino, A., Yang, X., et al. (2021). N6-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation. CANCER CELL, 39(7), 958-972 [10.1016/j.ccell.2021.04.017].

N6-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation

Savino, Angela M;
2021

Abstract

N6-Methyladenosine (m6A) on mRNAs mediates different biological processes and its dysregulation contributes to tumorigenesis. How m6A dictates its diverse molecular and cellular effects in leukemias remains unknown. We found that YTHDC1 is the essential m6A reader in myeloid leukemia from a genome-wide CRISPR screen and that m6A is required for YTHDC1 to undergo liquid-liquid phase separation and form nuclear YTHDC1-m6A condensates (nYACs). The number of nYACs increases in acute myeloid leukemia (AML) cells compared with normal hematopoietic stem and progenitor cells. AML cells require the nYACs to maintain cell survival and the undifferentiated state that is critical for leukemia maintenance. Furthermore, nYACs enable YTHDC1 to protect m6A-mRNAs from the PAXT complex and exosome-associated RNA degradation. Collectively, m6A is required for the formation of a nuclear body mediated by phase separation that maintains mRNA stability and control cancer cell survival and differentiation.
Si
Articolo in rivista - Articolo scientifico
Scientifica
differentiation; myeloid leukemia; phase separation; RNA methylation; RNA-binding proteins;
English
958
972
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Cheng, Y., Xie, W., Pickering, B., Chu, K., Savino, A., Yang, X., et al. (2021). N6-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation. CANCER CELL, 39(7), 958-972 [10.1016/j.ccell.2021.04.017].
Cheng, Y; Xie, W; Pickering, B; Chu, K; Savino, A; Yang, X; Luo, H; Nguyen, D; Mo, S; Barin, E; Velleca, A; Rohwetter, T; Patel, D; Jaffrey, S; Kharas, M
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/391388
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