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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 755-763 |
| Number of pages | 9 |
| Journal | Nature |
| Volume | 616 |
| Issue number | 7958 |
| DOIs | |
| State | Published - Apr 27 2023 |
Funding
WGS for the TOPMed programme was supported by the National Heart, Lung and Blood Institute (NHLBI). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity quality control and general study coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). The authors thank the studies and participants who provided biological samples and data for TOPMed. The full study-specific acknowledgments are included in Supplementary Note 4. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services. The authors wish to acknowledge the contributions of the consortium working on the development of the NHLBI BioData Catalyst ecosystem. S.J. is supported by the Burroughs Wellcome Foundation Career Award for Medical Scientists, Foundation Leducq (TNE-18CVD04), Ludwig Center for Cancer Stem Cell Research, the American Society of Hematology Scholar Award, the NIH Director’s New Innovator Award (DP2-HL157540), and a Leukemia and Lymphoma Society Discovery Grant. A.G.B. is supported by a Burroughs Wellcome Foundation Career Award for Medical Scientists, the NIH Director’s Early Independence Award (DP5-OD029586), and the Pew-Stewart Scholar for Cancer Research award, supported by the Pew Charitable Trusts and the Alexander and Margaret Stewart Trust. WHI CHIP amplicon sequencing was supported by the NHLBI (R01 HL148565). The Fred Hutchinson Cooperative Center of Excellence in Hematology cell collection and processing is supported by NIDDK Grant # DK106829. The authors thank R. Majeti, T. Koehnke and B. Ebert for helpful discussions. WGS for the TOPMed programme was supported by the National Heart, Lung and Blood Institute (NHLBI). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity quality control and general study coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). The authors thank the studies and participants who provided biological samples and data for TOPMed. The full study-specific acknowledgments are included in Supplementary Note . The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services. The authors wish to acknowledge the contributions of the consortium working on the development of the NHLBI BioData Catalyst ecosystem. S.J. is supported by the Burroughs Wellcome Foundation Career Award for Medical Scientists, Foundation Leducq (TNE-18CVD04), Ludwig Center for Cancer Stem Cell Research, the American Society of Hematology Scholar Award, the NIH Director’s New Innovator Award (DP2-HL157540), and a Leukemia and Lymphoma Society Discovery Grant. A.G.B. is supported by a Burroughs Wellcome Foundation Career Award for Medical Scientists, the NIH Director’s Early Independence Award (DP5-OD029586), and the Pew-Stewart Scholar for Cancer Research award, supported by the Pew Charitable Trusts and the Alexander and Margaret Stewart Trust. WHI CHIP amplicon sequencing was supported by the NHLBI (R01 HL148565). The Fred Hutchinson Cooperative Center of Excellence in Hematology cell collection and processing is supported by NIDDK Grant # DK106829. The authors thank R. Majeti, T. Koehnke and B. Ebert for helpful discussions.
ASJC Scopus subject areas
- General