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Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis

Weinstock, J.S. ; Konkle, B.A. ; Johnsen, J.M. ; Smith, J.G. LU ; Melander, O. LU orcid ; Nilsson, P.M. LU and Jaiswal, S. (2023) In Nature 616(7958). p.755-763
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... (More)
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. © 2023. The Author(s), under exclusive licence to Springer Nature Limited. (Less)
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type
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published
subject
keywords
animal, clonal hematopoiesis, genetics, genome-wide association study, hematopoiesis, hematopoietic stem cell, human, metabolism, mouse, mutation, Animals, Clonal Hematopoiesis, Genome-Wide Association Study, Hematopoiesis, Hematopoietic Stem Cells, Humans, Mice, Mutation
in
Nature
volume
616
issue
7958
pages
9 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85153988199
  • pmid:37046083
ISSN
1476-4687
DOI
10.1038/s41586-023-05806-1
language
English
LU publication?
yes
id
51babf53-932c-4d12-9728-7617d858c9b0
date added to LUP
2023-11-09 09:02:37
date last changed
2024-01-06 04:50:18
@article{51babf53-932c-4d12-9728-7617d858c9b0,
  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. © 2023. The Author(s), under exclusive licence to Springer Nature Limited.}},
  author       = {{Weinstock, J.S. and Konkle, B.A. and Johnsen, J.M. and Smith, J.G. and Melander, O. and Nilsson, P.M. and Jaiswal, S.}},
  issn         = {{1476-4687}},
  keywords     = {{animal; clonal hematopoiesis; genetics; genome-wide association study; hematopoiesis; hematopoietic stem cell; human; metabolism; mouse; mutation; Animals; Clonal Hematopoiesis; Genome-Wide Association Study; Hematopoiesis; Hematopoietic Stem Cells; Humans; Mice; Mutation}},
  language     = {{eng}},
  number       = {{7958}},
  pages        = {{755--763}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature}},
  title        = {{Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis}},
  url          = {{http://dx.doi.org/10.1038/s41586-023-05806-1}},
  doi          = {{10.1038/s41586-023-05806-1}},
  volume       = {{616}},
  year         = {{2023}},
}