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Gustav Smith, MD, PhD

Gustav Smith

Associate professor

Gustav Smith, MD, PhD

Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis

Author

  • J.S. Weinstock
  • B.A. Konkle
  • J.M. Johnsen
  • J.G. Smith
  • O. Melander
  • P.M. Nilsson
  • S. Jaiswal

Summary, in English

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.

Department/s

  • WCMM-Wallenberg Centre for Molecular Medicine
  • Heart Failure and Mechanical Support
  • Cardiovascular Epigenetics
  • Cardiology
  • EpiHealth: Epidemiology for Health
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Molecular Epidemiology and Cardiology
  • Cardiovascular Research - Hypertension
  • MultiPark: Multidisciplinary research focused on Parkinson´s disease
  • Internal Medicine - Epidemiology

Publishing year

2023

Language

English

Pages

755-763

Publication/Series

Nature

Volume

616

Issue

7958

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Medical Genetics

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

Status

Published

Research group

  • Heart Failure and Mechanical Support
  • Cardiovascular Epigenetics
  • Molecular Epidemiology and Cardiology
  • Cardiovascular Research - Hypertension
  • Internal Medicine - Epidemiology

ISBN/ISSN/Other

  • ISSN: 1476-4687