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Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells

Bao, Erik L ; Nandakumar, Satish K ; Liao, Xiaotian ; Bick, Alexander G ; Karjalainen, Juha ; Tabaka, Marcin ; Gan, Olga I ; Havulinna, Aki S ; Kiiskinen, Tuomo T J and Lareau, Caleb A , et al. (2020) In Nature 586(7831). p.769-775
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... (More)

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.

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type
Contribution to journal
publication status
published
subject
in
Nature
volume
586
issue
7831
pages
7 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:33057200
  • scopus:85092577991
ISSN
0028-0836
DOI
10.1038/s41586-020-2786-7
language
English
LU publication?
yes
additional info
These authors contributed equally: Erik L. Bao, Satish K. Nandakumar, Xiaotian Liao.
id
6210d9bd-e1e9-48ed-8187-c10409fd1d09
date added to LUP
2021-01-17 19:05:21
date last changed
2024-03-05 19:31:26
@article{6210d9bd-e1e9-48ed-8187-c10409fd1d09,
  abstract     = {{<p>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 &lt; 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.</p>}},
  author       = {{Bao, Erik L and Nandakumar, Satish K and Liao, Xiaotian and Bick, Alexander G and Karjalainen, Juha and Tabaka, Marcin and Gan, Olga I and Havulinna, Aki S and Kiiskinen, Tuomo T J and Lareau, Caleb A and de Lapuente Portilla, Aitzkoa L and Li, Bo and Emdin, Connor and Codd, Veryan and Nelson, Christopher P and Walker, Christopher J and Churchhouse, Claire and de la Chapelle, Albert and Klein, Daryl E and Nilsson, Björn and Wilson, Peter W F and Cho, Kelly and Pyarajan, Saiju and Gaziano, J Michael and Samani, Nilesh J and Regev, Aviv and Palotie, Aarno and Neale, Benjamin M and Dick, John E and Natarajan, Pradeep and O'Donnell, Christopher J and Daly, Mark J and Milyavsky, Michael and Kathiresan, Sekar and Sankaran, Vijay G}},
  issn         = {{0028-0836}},
  language     = {{eng}},
  number       = {{7831}},
  pages        = {{769--775}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature}},
  title        = {{Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells}},
  url          = {{http://dx.doi.org/10.1038/s41586-020-2786-7}},
  doi          = {{10.1038/s41586-020-2786-7}},
  volume       = {{586}},
  year         = {{2020}},
}