Inherited blood cancer predisposition through altered transcription elongation.

Autor:	Zhao J; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Cancer Immunology, Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen, China. Electronic address: jw.zhao3@siat.ac.cn., Cato LD; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Arora UP; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Bao EL; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Bryant SC; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Williams N; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK; UK and MRC-Wellcome Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Jia Y; Harvard Stem Cell Institute, Cambridge, MA, USA; Stem Cell Program, Boston Children's Hospital, Boston, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA., Goldman SR; Nascent Transcriptomics Core, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Nangalia J; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK; UK and MRC-Wellcome Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Erb MA; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Vos SM; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, USA., Armstrong SA; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Sankaran VG; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA. Electronic address: sankaran@broadinstitute.org.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2024 Feb 01; Vol. 187 (3), pp. 642-658.e19. Date of Electronic Publication: 2024 Jan 12.
DOI:	10.1016/j.cell.2023.12.016
Abstrakt:	Despite advances in defining diverse somatic mutations that cause myeloid malignancies, a significant heritable component for these cancers remains largely unexplained. Here, we perform rare variant association studies in a large population cohort to identify inherited predisposition genes for these blood cancers. CTR9, which encodes a key component of the PAF1 transcription elongation complex, is among the significant genes identified. The risk variants found in the cases cause loss of function and result in a ∼10-fold increased odds of acquiring a myeloid malignancy. Partial CTR9 loss of function expands human hematopoietic stem cells (HSCs) by increased super elongation complex-mediated transcriptional activity, which thereby increases the expression of key regulators of HSC self-renewal. By following up on insights from a human genetic study examining inherited predisposition to the myeloid malignancies, we define a previously unknown antagonistic interaction between the PAF1 and super elongation complexes. These insights could enable targeted approaches for blood cancer prevention. Competing Interests: Declaration of interests M.A.E. serves as an advisor and has equity in Nexo Therapeutics. M.A.E. is an inventor on patent applications covering SR-0813. S.A.A. serves as an advisor and/or has equity in Neomorph Inc., Imago Biosciences, Cyteir Therapeutics, C4 Therapeutics, Nimbus Therapeutics, and Accent Therapeutics. S.A.A. receives research support from Janssen and Syndax. V.G.S. serves as an advisor to and/or has equity in Branch Biosciences, Ensoma, and Cellarity, all unrelated to the present work. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu