N 6 -Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation.

Autor:	Cheng Y; Molecular Pharmacology Program, Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Xie W; Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Pickering BF; Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY, USA., Chu KL; Molecular Pharmacology Program, Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA., Savino AM; Molecular Pharmacology Program, Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Yang X; Molecular Pharmacology Program, Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Luo H; Molecular Pharmacology Program, Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Nguyen DT; Molecular Pharmacology Program, Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Mo S; Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China., Barin E; Molecular Pharmacology Program, Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Velleca A; Molecular Pharmacology Program, Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Rohwetter TM; Molecular Pharmacology Program, Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Patel DJ; Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Jaffrey SR; Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY, USA., Kharas MG; Molecular Pharmacology Program, Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: kharasm@mskcc.org.
Jazyk:	angličtina
Zdroj:	Cancer cell [Cancer Cell] 2021 Jul 12; Vol. 39 (7), pp. 958-972.e8. Date of Electronic Publication: 2021 May 27.
DOI:	10.1016/j.ccell.2021.04.017
Abstrakt:	N 6 -Methyladenosine (m 6 A) on mRNAs mediates different biological processes and its dysregulation contributes to tumorigenesis. How m 6 A dictates its diverse molecular and cellular effects in leukemias remains unknown. We found that YTHDC1 is the essential m 6 A reader in myeloid leukemia from a genome-wide CRISPR screen and that m 6 A is required for YTHDC1 to undergo liquid-liquid phase separation and form nuclear YTHDC1-m 6 A 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 m 6 A-mRNAs from the PAXT complex and exosome-associated RNA degradation. Collectively, m 6 A is required for the formation of a nuclear body mediated by phase separation that maintains mRNA stability and control cancer cell survival and differentiation. Competing Interests: Declaration of interests S.R.J. is a scientific founder of Gotham Therapeutics and has equity in this company. D. J. P. is a consultant for Ventus Therapeutics. M.G.K. is a consultant for Accent Therapeutics and M.G.K.’s laboratory receives some financial support from 28-7. These disclosures are not directly related to these studies. There is a patent pending. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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