دورية أكاديمية
أعرض في EDS

Inherited blood cancer predisposition through altered transcription elongation.

التفاصيل البيبلوغرافية
العنوان: Inherited blood cancer predisposition through altered transcription elongation.
المؤلفون: 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.
المصدر: Cell [Cell] 2024 Feb 01; Vol. 187 (3), pp. 642-658.e19. Date of Electronic Publication: 2024 Jan 12.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Cell Press Country of Publication: United States NLM ID: 0413066 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4172 (Electronic) Linking ISSN: 00928674 NLM ISO Abbreviation: Cell Subsets: MEDLINE
أسماء مطبوعة: Publication: Cambridge, Ma : Cell Press
Original Publication: Cambridge, MIT Press.
مواضيع طبية MeSH: Hematologic Neoplasms*/genetics , Transcription Factors*/genetics , Phosphoproteins*/genetics , Transcription Elongation, Genetic*, Humans ; Hematopoietic Stem Cells/metabolism ; Nuclear Proteins/metabolism
مستخلص: 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.)
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معلومات مُعتمدة: R01 CA265726 United States CA NCI NIH HHS; T32 HL007574 United States HL NHLBI NIH HHS; P01 CA066996 United States CA NCI NIH HHS; R01 HL146500 United States HL NHLBI NIH HHS; R01 DK103794 United States DK NIDDK NIH HHS
فهرسة مساهمة: Keywords: CTR9; PAF1 complex; cancer predisposition; hematopoiesis; hematopoietic stem cells; myeloid malignancies; self-renewal; super elongation complex; transcription elongation
المشرفين على المادة: 0 (Nuclear Proteins)
0 (PAF1 protein, human)
0 (Transcription Factors)
0 (CTR9 protein, human)
0 (Phosphoproteins)
تواريخ الأحداث: Date Created: 20240113 Date Completed: 20240206 Latest Revision: 20240619
رمز التحديث: 20240619
مُعرف محوري في PubMed: PMC10872907
DOI: 10.1016/j.cell.2023.12.016
PMID: 38218188
قاعدة البيانات: MEDLINE
الوصف
تدمد:1097-4172
DOI:10.1016/j.cell.2023.12.016