Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells

FinnGen, 23andMe Research Team, Erik L. Bao, Satish K. Nandakumar, Xiaotian Liao, Alexander G. Bick, Juha Karjalainen, Marcin Tabaka, Olga I. Gan, Aki S. Havulinna, Tuomo T.J. Kiiskinen, Caleb A. Lareau, Aitzkoa L. de Lapuente Portilla, Bo Li, Connor Emdin, Veryan Codd, Christopher P. Nelson, Christopher J. Walker, Claire Churchhouse, Albert de la ChapelleDaryl E. Klein, Björn Nilsson, Peter W.F. Wilson, Kelly Cho, Jukka Partanen, Kimmo Savinainen, Veli Matti Kosma, Johanna Schleutker, Reijo Laaksonen, Jukka Peltola, Airi Jussila, Pia Isomäki, Tarja Laitinen, Hannu Kankaanranta, Mika Kähönen, Annika Auranen, Hannu Uusitalo, Hannele Uusitalo-Järvinen, Teea Salmi, Tiina Wahlfors, Arto Mannermaa, Juha Kononen, Hannele Laivuori, Anastasia Shcherban, Harri Siirtola, Javier Gracia Tabuenca

Research output: Contribution to journalArticleScientificpeer-review

8 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)769-775
Number of pages7
Issue number7831
Publication statusPublished - Oct 2020
Publication typeA1 Journal article-refereed

Publication forum classification

  • Publication forum level 3

ASJC Scopus subject areas

  • General


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