Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis

Joshua S. Weinstock, Jayakrishnan Gopakumar, Bala Bharathi Burugula, Md Mesbah Uddin, Nikolaus Jahn, Julia A. Belk, Hind Bouzid, Bence Daniel, Zhuang Miao, Nghi Ly, Taralynn M. Mack, Sofia E. Luna, Katherine P. Prothro, Shaneice R. Mitchell, Cecelia A. Laurie, Jai G. Broome, Kent D. Taylor, Xiuqing Guo, Moritz F. Sinner, Aenne S. Falkenhausen, Stefan Kääb, Alan R. Shuldiner, Jeffrey R. O’Connell, Joshua P. Lewis, Eric Boerwinkle, Kathleen C. Barnes, Nathalie Chami, Eimear E. Kenny, Ruth J. F. Loos, Myriam Fornage, Lifang Hou, Donald M. Lloyd-Jones, Susan Redline, Brian E. Cade, Bruce M. Psaty, Joshua C. Bis, Jennifer A. Brody, Edwin K. Silverman, Jeong H. Yun, Dandi Qiao, Nicholette D. Palmer, Barry I. Freedman, Donald W. Bowden, Michael H. Cho, Dawn L. DeMeo, Ramachandran S. Vasan, Lisa R. Yanek, Lewis C. Becker, Sharon L. R. Kardia, Patricia A. Peyser, Jiang He, Michiel Rienstra, Pim Harst, Robert Kaplan, Susan R. Heckbert, Nicholas L. Smith, Kerri L. Wiggins, Donna K. Arnett, Marguerite R. Irvin, Hemant Tiwari, Michael J. Cutler, Stacey Knight, J. Brent Muhlestein, Adolfo Correa, Laura M. Raffield, Yan Gao, Mariza Andrade, Jerome I. Rotter, Stephen S. Rich, Russell P. Tracy, Barbara A. Konkle, Jill M. Johnsen, Marsha M. Wheeler, J. Gustav Smith, Olle Melander, Peter M. Nilsson, Brian S. Custer, Ravindranath Duggirala, Joanne E. Curran, John Blangero, Stephen McGarvey, L. Keoki Williams, Shujie Xiao, Mao Yang, C. Charles Gu, Yii- Der Ida Chen, Wen-Jane Lee, Gregory M. Marcus, John P. Kane, Clive R. Pullinger, M. Benjamin Shoemaker, Dawood Darbar, Dan M. Roden, Christine Albert, Charles Kooperberg, Ying Zhou, JoAnn E. Manson, Pinkal Desai, Andrew D. Johnson, Rasika A. Mathias, Thomas W. Blackwell, Goncalo R. Abecasis, Albert V. Smith, Hyun M. Kang, Ansuman T. Satpathy, Pradeep Natarajan, Jacob O. Kitzman, Eric A. Whitsel, Alexander P. Reiner, Alexander G. Bick () and Siddhartha Jaiswal ()
Additional contact information
Joshua S. Weinstock: University of Michigan School of Public Health
Jayakrishnan Gopakumar: Stanford University School of Medicine
Bala Bharathi Burugula: University of Michigan
Md Mesbah Uddin: Broad Institute of Harvard and MIT
Nikolaus Jahn: Stanford University School of Medicine
Julia A. Belk: Stanford University School of Medicine
Hind Bouzid: Stanford University School of Medicine
Bence Daniel: Stanford University School of Medicine
Zhuang Miao: Stanford University School of Medicine
Nghi Ly: Stanford University School of Medicine
Taralynn M. Mack: Vanderbilt University
Sofia E. Luna: Stanford University School of Medicine
Katherine P. Prothro: Stanford University School of Medicine
Shaneice R. Mitchell: Stanford University School of Medicine
Cecelia A. Laurie: University of Washington
Jai G. Broome: University of Washington
Kent D. Taylor: The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor–UCLA Medical Center
Xiuqing Guo: The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor–UCLA Medical Center
Moritz F. Sinner: University Hospital, LMU Munich
Aenne S. Falkenhausen: University Hospital, LMU Munich
Stefan Kääb: University Hospital, LMU Munich
Alan R. Shuldiner: University of Maryland, Baltimore
Jeffrey R. O’Connell: University of Maryland, Baltimore
Joshua P. Lewis: University of Maryland, Baltimore
Eric Boerwinkle: Baylor College of Medicine
Kathleen C. Barnes: University of Colorado Anschutz Medical Campus
Nathalie Chami: The Charles Bronfman Institute of Personalized Medicine
Eimear E. Kenny: Institute for Genomic Health
Ruth J. F. Loos: The Charles Bronfman Institute of Personalized Medicine
Myriam Fornage: University of Texas Health at Houston
Lifang Hou: Northeastern University
Donald M. Lloyd-Jones: Northeastern University
Susan Redline: Brigham and Women’s Hospital
Brian E. Cade: Broad Institute of Harvard and MIT
Bruce M. Psaty: University of Washington
Joshua C. Bis: University of Washington
Jennifer A. Brody: University of Washington
Edwin K. Silverman: Brigham and Women’s Hospital
Jeong H. Yun: Brigham and Women’s Hospital
Dandi Qiao: Brigham and Women’s Hospital
Nicholette D. Palmer: Wake Forest School of Medicine
Barry I. Freedman: Wake Forest School of Medicine
Donald W. Bowden: Wake Forest School of Medicine
Michael H. Cho: Brigham and Women’s Hospital
Dawn L. DeMeo: Brigham and Women’s Hospital
Ramachandran S. Vasan: Boston University’s Framingham Heart Study
Lisa R. Yanek: Johns Hopkins University School of Medicine
Lewis C. Becker: Johns Hopkins University School of Medicine
Sharon L. R. Kardia: University of Michigan
Patricia A. Peyser: University of Michigan
Jiang He: Tulane University School of Public Health and Tropical Medicine
Michiel Rienstra: University of Groningen, University Medical Center Groningen
Pim Harst: University of Groningen, University Medical Center Groningen
Robert Kaplan: Albert Einstein College of Medicine
Susan R. Heckbert: University of Washington
Nicholas L. Smith: University of Washington
Kerri L. Wiggins: University of Washington
Donna K. Arnett: University of Kentucky
Marguerite R. Irvin: University of Alabama at Birmingham
Hemant Tiwari: University of Alabama
Michael J. Cutler: Intermountain Medical Center
Stacey Knight: Intermountain Medical Center
J. Brent Muhlestein: Intermountain Medical Center
Adolfo Correa: University of Mississippi Medical Center
Laura M. Raffield: University of North Carolina at Chapel Hill
Yan Gao: University of Mississippi Medical Center
Mariza Andrade: Mayo Clinic
Jerome I. Rotter: The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor–UCLA Medical Center
Stephen S. Rich: University of Virginia
Russell P. Tracy: Larner College of Medicine at the University of Vermont
Barbara A. Konkle: Lund University and Skåne University Hospital
Jill M. Johnsen: Lund University and Skåne University Hospital
Marsha M. Wheeler: University of Washington
J. Gustav Smith: Lund University and Skåne University Hospital
Olle Melander: Lund University and Skane University Hospital
Peter M. Nilsson: Lund University and Skane University Hospital
Brian S. Custer: Vitalant Research Institute
Ravindranath Duggirala: University of Texas Rio Grande Valley School of Medicine
Joanne E. Curran: University of Texas Rio Grande Valley School of Medicine
John Blangero: University of Texas Rio Grande Valley School of Medicine
Stephen McGarvey: Brown University School of Public Health
L. Keoki Williams: Henry Ford Health System
Shujie Xiao: Henry Ford Health System
Mao Yang: Henry Ford Health System
C. Charles Gu: Washington University School of Medicine
Yii- Der Ida Chen: The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor–UCLA Medical Center
Wen-Jane Lee: Taichung Veterans General Hospital
Gregory M. Marcus: University of California, San Francisco
John P. Kane: University of California, San Francisco
Clive R. Pullinger: University of California
M. Benjamin Shoemaker: Vanderbilt University Medical Center
Dawood Darbar: University of Illinois at Chicago
Dan M. Roden: Vanderbilt University Medical Center
Christine Albert: Cedars-Sinai
Charles Kooperberg: Fred Hutchinson Cancer Research Center
Ying Zhou: Fred Hutchinson Cancer Research Center
JoAnn E. Manson: Brigham and Women’s Hospital
Pinkal Desai: Weill Cornell Medicine
Andrew D. Johnson: Population Sciences Branch
Rasika A. Mathias: Johns Hopkins University School of Medicine
Thomas W. Blackwell: University of Michigan School of Public Health
Goncalo R. Abecasis: University of Michigan School of Public Health
Albert V. Smith: University of Michigan School of Public Health
Hyun M. Kang: University of Michigan School of Public Health
Ansuman T. Satpathy: Stanford University School of Medicine
Pradeep Natarajan: Broad Institute of Harvard and MIT
Jacob O. Kitzman: University of Michigan
Eric A. Whitsel: University of North Carolina
Alexander P. Reiner: Broad Institute
Alexander G. Bick: Vanderbilt University
Siddhartha Jaiswal: Stanford University School of Medicine

Nature, 2023, vol. 616, issue 7958, 755-763

Abstract: Abstract Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2–6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

Date: 2023
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DOI: 10.1038/s41586-023-05806-1

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