Clonal hematopoiesis is driven by aberrant activation of TCL1A
Clonal hematopoiesis is driven by aberrant activation of TCL1A
Abstract A diverse set of driver genes, such as regulators of DNA methylation, RNA splicing, and chromatin remodeling, have been associated with pre-malignant clonal expansion of hematopoietic stem cells (HSCs). The factors mediating expansion of these mutant clones remain largely unknown, partially due to a paucity of large cohorts with longitudinal blood sampling. To circumvent this limitation, we developed and validated a method to infer clonal expansion rate from single timepoint data called PACER (passenger-approximated clonal expansion rate). Applying PACER to 5,071 persons with clonal hematopoiesis accurately recapitulated the known fitness effects due to different driver mutations. A genome-wide association study of PACER revealed that a common inherited polymorphism in the TCL1A promoter was associated with slower clonal expansion. Those carrying two copies of this protective allele had up to 80% reduced odds of having driver mutations in TET2, ASXL1, SF3B1, SRSF2, and JAK2, but not DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 by CRISPR editing led to aberrant expression of TCL1A and expansion of HSCs in vitro. These effects were abrogated in HSCs from donors carrying the protective TCL1A allele. Our results indicate that the fitness advantage of multiple common driver genes in clonal hematopoiesis is mediated through TCL1A activation. PACER is an approach that can be widely applied to uncover genetic and environmental determinants of pre-malignant clonal expansion in blood and other tissues.
Yun Jeong H.、Lewis Joshua P.、Shuldiner Alan R.、Mathias Rasika、Lloyd-Jones Donald M.、Yanek Lisa R.、Melander Olle、Psaty Bruce M.、Darbar Dawood、Kooperberg Charles、Smith Albert V.、Kane John P.、Kang Hyun M.、Whitsel Eric、Reiner Alexander P.、Raffield Laura M.、Loos Ruth J.、Taylor Kent D.、Sinner Moritz F.、von Falkenhausen Aenne S.、O?ˉConnell Jeffrey R.、Weinstock Joshua S.、McGarvey Stephen、Williams L. Keoki、Yang Mao、Gu C. Charles.、Pullinger Clive R.、Shoemaker M. Benjamin、Redline Susan、Brody Jennifer A.、Palmer Nicholette D.、DeMeo Dawn L.、Peyser Patricia A.、Rienstra Michiel、Smith Nicholas L.、Wiggins Kerri L.、Arnett Donna K.、Irvin Marguerite R.、Tiwari Hemant、Muhlestein J Brent.、Satpathy Ansuman T.、Konkle Barbara A.、Wheeler Marsha M.、Duggirala Ravindranath、Curran Joanne E.、Laurie Cecelia A.、Qiao Dandi、Bis Joshua C.、Correa Adolfo、Cutler Michael J.、Desai Pinkal、Fornage Myriam、Becker Lewis C.、Albert Christine、Cade Brian E.、Knight Stacey、Broome Jai G.、Harst Pim Van der、Chami Nathalie、Ly Nghi、Hou Lifang、Kenny Eimear E.、Jahn Nikolaus、Freedman Barry I.、Vasan Ramachandran S.、Kitzman Jacob、Gao Yan、Johnsen Jill M.、K??b Stefan、Rotter Jerome I.、Roden Dan、Tracy Russell P.、Marcus Gregory M.、Chen Yii-Der Ida.、Boerwinkle Eric、Johnson Andrew、Andrade Mariza de、Bick Alexander G.、Abecasis Goncalo R.、Kaplan Robert、Silverman Edwin K.、Gopakumar Jayakrishnan、He Jiang、Manson JoAnn E.、Burugula Bala Bharathi、Barnes Kathleen C.、Uddin Md Mesbah、Xiao Shujie、Custer Brian S.、Zhou Ying、Daniel Bence、Bowden Donald W.、Cho Michael H.、Rich Stephen S.、Heckbert Susan R.、Guo Xiuqing、Jaiswal Sidd、Smith J. Gustav、Mack Taralyn M.、Natarajan Pradeep、Nilsson Peter M.、Belk Julia A.、Blangero John、Blackwell Thomas W.、Kardia Sharon、Lee Wen-Jane
Channing Division of Network Medicine, Brigham and Women?ˉs HospitalDepartmant of Medicine, University of MarylandDepartmant of Medicine, University of MarylandDepartment of Medicine, Johns Hopkins University School of MedicineDepartment of Preventive Medicine, Northestern UniversityDepartment of Medicine, Johns Hopkins University School of MedicineDepartment of Internal Medicine, Clinical Sciences, Lund University and Skane University HospitalCardiovascular Health Research Unit, Department of Medicine, University of Washington||Department of Epidemiology, University of Washington||Department of Medicine, University of WashingtonDivision of Cardiology, University of Illinois at ChicagoDivision of Public Health Sciences, Fred Hutchinson Cancer Research CenterCenter for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public HealthDepartment of Medicine, Cardiovascular Research Institute, University of CaliforniaCenter for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public HealthDepartment of Epidemiology, Gillings School of Global Public Health, University of North CarolinaDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center||Department of Epidemiology, University of WashingtonDepartment of Genetics, University of North Carolina at Chapel HillThe Charles Bronfman Institute of Personalized Medicine||The Mindich Child Health and Developlement Institute, Icahn School of Medicine at Mount SinaiThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterDepartment of Medicine I, University Hospital, LMU Munich||German Centre for Cardiovascular Research (DZHK), partner site: Munich Heart AllianceDepartment of Medicine I, University Hospital, LMU Munich||German Centre for Cardiovascular Research (DZHK), partner site: Munich Heart AllianceDepartmant of Medicine, University of MarylandCenter for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public HealthDepartment of Epidemiology and International Health Institute, Brown University School of Public HealthCenter for Individualized and Genomic Medicine Research (CIGMA), Department of Internal Medicine, Henry Ford Health SystemCenter for Individualized and Genomic Medicine Research (CIGMA), Department of Internal Medicine, Henry Ford Health SystemDivision of Biostatistics, Campus Box 8067 Washington University School of Medicine 660 S. Euclid Avenue St. LouisCardiovascular Research Institute, University of CaliforniaDivision of Cardiology, Vanderbilt University Medical CenterDepartment of Medicine, Brigham and Women?ˉs Hospital||Harvard Medical SchoolCardiovascular Health Research Unit, Department of Medicine, University of WashingtonDepartment of Biochemistry, Wake Forest School of MedicineChanning Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women?ˉs HospitalDepartment of Epidemiology, School of Public Health, University of MichiganDepartment of Cardiology, University of Groningen, University Medical Center GroningenDepartment of Epidemiology, University of Washington||Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington||??¤ Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and DevelopmentCardiovascular Health Research Unit, Department of Medicine, University of WashingtonDean?ˉs Office, College of Public Health, University of KentuckyUniversity of Alabama at BirminghamUniversity of Alabama at BirminghamIntermountain Heart Institute, Intermountain Medical CenterDepartment of Pathology, Stanford University School of MedicineDepartment of Medicine, University of WashingtonGenome Science, University of WashingtonDepartment of Human Genetics, University of Texas Rio Grande Valley School of Medicine||South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of MedicineDepartment of Human Genetics, University of Texas Rio Grande Valley School of Medicine||South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of MedicineDepartment of Biostatistics, University of WashingtonChanning Division of Network Medicine, Brigham and Women?ˉs HospitalCardiovascular Health Research Unit, Department of Medicine, University of WashingtonDepartment of Medicine, Jackson Heart Study, University of Mississippi Medical CenterIntermountain Heart Institute, Intermountain Medical CenterDivision of Hematology&Oncology, Weill Cornell Medicine||Englander Institute of Prescision Medicine, Weill Cornell MedicineBrown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at HoustonDepartment of Medicine, Johns Hopkins University School of MedicineDepartment of CardiologyDepartment of Medicine, Brigham and Women?ˉs Hospital||Harvard Medical School||Program in Medical and Population Genetics, Broad Institute of Harvard & MITIntermountain Heart Institute, Intermountain Medical CenterDepartment of Biostatistics, University of Washington||Division of Medical Genetics, Department of Medicine, University of WashingtonDepartment of Cardiology, University of Groningen, University Medical Center GroningenThe Charles Bronfman Institute of Personalized Medicine||The Mindich Child Health and Developlement Institute, Icahn School of Medicine at Mount SinaiDepartment of Pathology, Stanford University School of MedicineDepartment of Preventive Medicine, Northestern UniversityInstitute for Genomic HealthDepartment of Pathology, Stanford University School of MedicineDepartment of Internal Medicine, Section on Nephrology, Wake Forest School of MedicineNational Heart Lung and Blood Institute?ˉs, Boston University?ˉs Framingham Heart StudyDepartment of Human Genetics, University of MichiganDepartment of Medicine, University of Mississippi Medical CenterResearch Institute, Bloodworks Northwest||Department of Medicine, University of WashingtonDepartment of Medicine I, University Hospital, LMU Munich||German Centre for Cardiovascular Research (DZHK), partner site: Munich Heart AllianceThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterDepartments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical CenterDepartment of Pathology & Laboratory Medicine and Biochemistry, Larner College of Medicine at the University of VermontDivision of Cardiology, University of CaliforniaThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterHuman Genome Sequencing Center, Baylor College of MedicineNational Heart, Lung and Blood Institute, Population Sciences Branch||Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of HealthMayo Clinic, Department of Health Sciences ResearchDivision of Genetic Medicine, Department of Medicine, Vanderbilt UniversityCenter for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health||Regeneron PharmaceuticalsAlbert Einstein College of Medicine, Department of Epidemiology and Population HealthChanning Division of Network Medicine, Brigham and Women?ˉs HospitalDepartment of Pathology, Stanford University School of MedicineDepartment of Epidemiology, Tulane University School of Public Health and Tropical MedcineDepartment of Medicine, Brigham and Women?ˉs Hospital and Harvard Medical SchoolDepartment of Human Genetics, University of MichiganDivision of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical CampusProgram in Medical and Population Genetics, Broad Institute of Harvard & MITCenter for Individualized and Genomic Medicine Research (CIGMA), Department of Internal Medicine, Henry Ford Health SystemVitalant Research InstituteDivision of Public Health Sciences, Fred Hutchinson Cancer Research CenterDepartment of Pathology, Stanford University School of MedicineDepartment of Biochemistry, Wake Forest School of MedicineChanning Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women?ˉs HospitalDepartment of Public Health Sciences, Center for Public Health Genomics, University of VirginiaDepartment of Epidemiology, University of Washington||Kaiser Permanente Washington Health Research Institute, Kaiser Permanente WashingtonThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterDepartment of Pathology, Stanford University School of Medicine||Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of MedicineDepartment of Cardiology, Clinical Sciences, Lund University and Sk?ne University Hospital||The Wallenberg Laboratory/Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University and the Department of Cardiology, Sahlgrenska University Hospital||Wallenberg Center for Molecular Medicine and Lund University Diabetes Center, Lund UniversityDivision of Genetic Medicine, Department of Medicine, Vanderbilt UniversityCardiovascular Research Center, Massachusetts General Hospital||Program in Medical and Population Genetics, Broad Institute of Harvard & MIT||Department of Medicine, Harvard Medical SchoolDepartment of Internal Medicine, Clinical Sciences, Lund University and Skane University HospitalDepartment of Pathology, Stanford University School of MedicineDepartment of Human Genetics, University of Texas Rio Grande Valley School of Medicine||South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of MedicineCenter for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public HealthDepartment of Epidemiology, School of Public Health, University of MichiganDepartment of Medical Research, Taichung Veterans General Hospital
基础医学生物科学研究方法、生物科学研究技术遗传学
Yun Jeong H.,Lewis Joshua P.,Shuldiner Alan R.,Mathias Rasika,Lloyd-Jones Donald M.,Yanek Lisa R.,Melander Olle,Psaty Bruce M.,Darbar Dawood,Kooperberg Charles,Smith Albert V.,Kane John P.,Kang Hyun M.,Whitsel Eric,Reiner Alexander P.,Raffield Laura M.,Loos Ruth J.,Taylor Kent D.,Sinner Moritz F.,von Falkenhausen Aenne S.,O?ˉConnell Jeffrey R.,Weinstock Joshua S.,McGarvey Stephen,Williams L. Keoki,Yang Mao,Gu C. Charles.,Pullinger Clive R.,Shoemaker M. Benjamin,Redline Susan,Brody Jennifer A.,Palmer Nicholette D.,DeMeo Dawn L.,Peyser Patricia A.,Rienstra Michiel,Smith Nicholas L.,Wiggins Kerri L.,Arnett Donna K.,Irvin Marguerite R.,Tiwari Hemant,Muhlestein J Brent.,Satpathy Ansuman T.,Konkle Barbara A.,Wheeler Marsha M.,Duggirala Ravindranath,Curran Joanne E.,Laurie Cecelia A.,Qiao Dandi,Bis Joshua C.,Correa Adolfo,Cutler Michael J.,Desai Pinkal,Fornage Myriam,Becker Lewis C.,Albert Christine,Cade Brian E.,Knight Stacey,Broome Jai G.,Harst Pim Van der,Chami Nathalie,Ly Nghi,Hou Lifang,Kenny Eimear E.,Jahn Nikolaus,Freedman Barry I.,Vasan Ramachandran S.,Kitzman Jacob,Gao Yan,Johnsen Jill M.,K??b Stefan,Rotter Jerome I.,Roden Dan,Tracy Russell P.,Marcus Gregory M.,Chen Yii-Der Ida.,Boerwinkle Eric,Johnson Andrew,Andrade Mariza de,Bick Alexander G.,Abecasis Goncalo R.,Kaplan Robert,Silverman Edwin K.,Gopakumar Jayakrishnan,He Jiang,Manson JoAnn E.,Burugula Bala Bharathi,Barnes Kathleen C.,Uddin Md Mesbah,Xiao Shujie,Custer Brian S.,Zhou Ying,Daniel Bence,Bowden Donald W.,Cho Michael H.,Rich Stephen S.,Heckbert Susan R.,Guo Xiuqing,Jaiswal Sidd,Smith J. Gustav,Mack Taralyn M.,Natarajan Pradeep,Nilsson Peter M.,Belk Julia A.,Blangero John,Blackwell Thomas W.,Kardia Sharon,Lee Wen-Jane.Clonal hematopoiesis is driven by aberrant activation of TCL1A[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/2021.12.10.471810.点此复制
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