Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis
Journal
Nature
Journal Volume
616
Journal Issue
7958
Date Issued
2023-04
Author(s)
Weinstock, Joshua S
Gopakumar, Jayakrishnan
Burugula, Bala Bharathi
Uddin, Md Mesbah
Jahn, Nikolaus
Belk, Julia A
Bouzid, Hind
Daniel, Bence
Miao, Zhuang
Ly, Nghi
Mack, Taralynn M
Luna, Sofia E
Prothro, Katherine P
Mitchell, Shaneice R
Laurie, Cecelia A
Broome, Jai G
Taylor, Kent D
Guo, Xiuqing
Sinner, Moritz F
von Falkenhausen, Aenne S
Kääb, Stefan
Shuldiner, Alan R
O'Connell, Jeffrey R
Lewis, Joshua P
Boerwinkle, Eric
Barnes, Kathleen C
Chami, Nathalie
Kenny, Eimear E
Loos, Ruth J F
Fornage, Myriam
Hou, Lifang
Lloyd-Jones, Donald M
Redline, Susan
Cade, Brian E
Psaty, Bruce M
Bis, Joshua C
Brody, Jennifer A
Silverman, Edwin K
Yun, Jeong H
Qiao, Dandi
Palmer, Nicholette D
Freedman, Barry I
Bowden, Donald W
Cho, Michael H
DeMeo, Dawn L
Vasan, Ramachandran S
Yanek, Lisa R
Becker, Lewis C
Kardia, Sharon L R
Peyser, Patricia A
He, Jiang
Rienstra, Michiel
Van der Harst, Pim
Kaplan, Robert
Heckbert, Susan R
Smith, Nicholas L
Wiggins, Kerri L
Arnett, Donna K
Irvin, Marguerite R
Tiwari, Hemant
Cutler, Michael J
Knight, Stacey
Muhlestein, J Brent
Correa, Adolfo
Raffield, Laura M
Gao, Yan
de Andrade, Mariza
Rotter, Jerome I
Rich, Stephen S
Tracy, Russell P
Konkle, Barbara A
Johnsen, Jill M
Wheeler, Marsha M
Smith, J Gustav
Melander, Olle
Nilsson, Peter M
Custer, Brian S
Duggirala, Ravindranath
Curran, Joanne E
Blangero, John
McGarvey, Stephen
Williams, L Keoki
Xiao, Shujie
Yang, Mao
Gu, C Charles
Chen, Yii-Der Ida
Lee, Wen-Jane
Marcus, Gregory M
Kane, John P
Pullinger, Clive R
Shoemaker, M Benjamin
Darbar, Dawood
Roden, Dan M
Albert, Christine
Kooperberg, Charles
Zhou, Ying
Manson, JoAnn E
Desai, Pinkal
Johnson, Andrew D
Mathias, Rasika A
Blackwell, Thomas W
Abecasis, Goncalo R
Smith, Albert V
Kang, Hyun M
Satpathy, Ansuman T
Natarajan, Pradeep
Kitzman, Jacob O
Whitsel, Eric A
Reiner, Alexander P
Bick, Alexander G
Jaiswal, Siddhartha
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.
SDGs
Type
journal article