Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells

Research output: Contribution to journalArticle

Abstract

Myeloproliferative neoplasms (MPNs) are blood cancers that are characterized by the excessive production of mature myeloid cells and arise from the acquisition of somatic driver mutations in haematopoietic stem cells (HSCs). Epidemiological studies indicate a substantial heritable component of MPNs that is among the highest known for cancers1. However, only a limited number of genetic risk loci have been identified, and the underlying biological mechanisms that lead to the acquisition of MPNs remain unclear. Here, by conducting a large-scale genome-wide association study (3,797 cases and 1,152,977 controls), we identify 17 MPN risk loci (P < 5.0 × 10-8), 7 of which have not been previously reported. We find that there is a shared genetic architecture between MPN risk and several haematopoietic traits from distinct lineages; that there is an enrichment for MPN risk variants within accessible chromatin of HSCs; and that increased MPN risk is associated with longer telomere length in leukocytes and other clonal haematopoietic states-collectively suggesting that MPN risk is associated with the function and self-renewal of HSCs. We use gene mapping to identify modulators of HSC biology linked to MPN risk, and show through targeted variant-to-function assays that CHEK2 and GFI1B have roles in altering the function of HSCs to confer disease risk. Overall, our results reveal a previously unappreciated mechanism for inherited MPN risk through the modulation of HSC function.

Details

Authors
Organisations
External organisations
  • Harvard Medical School
  • Massachusetts General Hospital
  • Glenfield Hospital
  • Ohio State University
  • Yale University
  • Dana-Farber Cancer Institute
  • Massachusetts Institute of Technology
  • University of Helsinki
  • University of Toronto
  • Brigham and Women's Hospital, Boston
  • Tel-Aviv University
  • Broad Institute
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
  • Hematology
Original languageEnglish
Pages (from-to)769-775
Number of pages7
JournalNature
Volume586
Issue number7831
Publication statusPublished - 2020 Oct
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

These authors contributed equally: Erik L. Bao, Satish K. Nandakumar, Xiaotian Liao.