RNA sequestration in P-bodies sustains myeloid leukaemia.

Autor: Kodali S; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA.; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.; Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Proietti L; Institute for Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, Austria., Valcarcel G; Josep Carreras Leukaemia Research Institute, Badalona, Spain., López-Rubio AV; Josep Carreras Leukaemia Research Institute, Badalona, Spain., Pessina P; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA.; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.; Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Eder T; Institute for Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, Austria., Shi J; Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, USA., Jen A; Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI, USA., Lupión-Garcia N; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA.; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.; Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Starner AC; Verna & Marrs McLean Department of Biochemistry & Molecular Biology and Therapeutic Innovation Center, Baylor College of Medicine, Houston, TX, USA., Bartels MD; Verna & Marrs McLean Department of Biochemistry & Molecular Biology and Therapeutic Innovation Center, Baylor College of Medicine, Houston, TX, USA., Cui Y; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA.; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.; Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Sands CM; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA.; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.; Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Planas-Riverola A; Josep Carreras Leukaemia Research Institute, Badalona, Spain., Martínez A; Josep Carreras Leukaemia Research Institute, Badalona, Spain., Velasco-Hernandez T; Josep Carreras Leukaemia Research Institute, Badalona, Spain., Tomás-Daza L; Josep Carreras Leukaemia Research Institute, Badalona, Spain., Alber B; Institute for Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, Austria., Manhart G; Institute for Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, Austria., Mayer IM; Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria., Kollmann K; Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria., Fatica A; Department of Biology and Biotechnology 'Charles Darwin', Sapienza University of Rome, Rome, Italy., Menendez P; Josep Carreras Leukaemia Research Institute, Badalona, Spain., Shishkova E; Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI, USA.; National Center for Quantitative Biology of Complex Systems, Madison, WI, USA., Rau RE; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA.; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.; Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA., Javierre BM; Josep Carreras Leukaemia Research Institute, Badalona, Spain., Coon J; Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI, USA.; National Center for Quantitative Biology of Complex Systems, Madison, WI, USA.; Department of Chemistry, University of Wisconsin, Madison, WI, USA.; Morgridge Institute for Research, Madison, WI, USA., Chen Q; Molecular Medicine Program, Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA., Van Nostrand EL; Verna & Marrs McLean Department of Biochemistry & Molecular Biology and Therapeutic Innovation Center, Baylor College of Medicine, Houston, TX, USA., Sardina JL; Josep Carreras Leukaemia Research Institute, Badalona, Spain. jsardina@carrerasresearch.org., Grebien F; Institute for Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, Austria. Florian.Grebien@vetmeduni.ac.at.; St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria. Florian.Grebien@vetmeduni.ac.at.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. Florian.Grebien@vetmeduni.ac.at., Di Stefano B; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA. bruno.distefano@bcm.edu.; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA. bruno.distefano@bcm.edu.; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. bruno.distefano@bcm.edu.; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. bruno.distefano@bcm.edu.; Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. bruno.distefano@bcm.edu.
Jazyk: angličtina
Zdroj: Nature cell biology [Nat Cell Biol] 2024 Oct; Vol. 26 (10), pp. 1745-1758. Date of Electronic Publication: 2024 Aug 21.
DOI: 10.1038/s41556-024-01489-6
Abstrakt: Post-transcriptional mechanisms are fundamental safeguards of progenitor cell identity and are often dysregulated in cancer. Here, we identified regulators of P-bodies as crucial vulnerabilities in acute myeloid leukaemia (AML) through genome-wide CRISPR screens in normal and malignant haematopoietic progenitors. We found that leukaemia cells harbour aberrantly elevated numbers of P-bodies and show that P-body assembly is crucial for initiation and maintenance of AML. Notably, P-body loss had little effect upon homoeostatic haematopoiesis but impacted regenerative haematopoiesis. Molecular characterization of P-bodies purified from human AML cells unveiled their critical role in sequestering messenger RNAs encoding potent tumour suppressors from the translational machinery. P-body dissolution promoted translation of these mRNAs, which in turn rewired gene expression and chromatin architecture in leukaemia cells. Collectively, our findings highlight the contrasting and unique roles of RNA sequestration in P-bodies during tissue homoeostasis and oncogenesis. These insights open potential avenues for understanding myeloid leukaemia and future therapeutic interventions.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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