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. von 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 Van der 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 de 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
Keoki L. Williams, Henry Ford HealthFollow
Shujie Xiao, Henry Ford HealthFollow
Mao Yang, Henry Ford HealthFollow
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
Siddhartha Jaiswal

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Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis(1). These lesions are precursors for blood cancers(2-6), 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.

Medical Subject Headings

Animals; Humans; Mice; Alleles; Clonal Hematopoiesis; Genome-Wide Association Study; Hematopoiesis; Hematopoietic Stem Cells; Mutation; Promoter Regions, Genetic

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