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  • Bao, Erik LHarvard Medical School (author)

Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells

  • Article/chapterEnglish2020

Publisher, publication year, extent ...

  • 2020-10-14
  • Springer Science and Business Media LLC,2020
  • 7 s.

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:6210d9bd-e1e9-48ed-8187-c10409fd1d09
  • https://lup.lub.lu.se/record/6210d9bd-e1e9-48ed-8187-c10409fd1d09URI
  • https://doi.org/10.1038/s41586-020-2786-7DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • 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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Added entries (persons, corporate bodies, meetings, titles ...)

  • Nandakumar, Satish KHarvard Medical School (author)
  • Liao, XiaotianHarvard Medical School (author)
  • Bick, Alexander GMassachusetts Institute of Technology (author)
  • Karjalainen, JuhaUniversity of Helsinki (author)
  • Tabaka, MarcinMassachusetts Institute of Technology (author)
  • Gan, Olga IUniversity of Toronto (author)
  • Havulinna, Aki SUniversity of Helsinki (author)
  • Kiiskinen, Tuomo T JUniversity of Helsinki (author)
  • Lareau, Caleb AHarvard Medical School (author)
  • de Lapuente Portilla, Aitzkoa LLund University,Lunds universitet,Avdelningen för hematologi och transfusionsmedicin,Institutionen för laboratoriemedicin,Medicinska fakulteten,Hematogenomics,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Hematology and Transfusion Medicine,Department of Laboratory Medicine,Faculty of Medicine,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments(Swepub:lu)med-azl (author)
  • Li, BoMassachusetts Institute of Technology,Massachusetts General Hospital (author)
  • Emdin, ConnorMassachusetts Institute of Technology (author)
  • Codd, VeryanGlenfield Hospital (author)
  • Nelson, Christopher PGlenfield Hospital (author)
  • Walker, Christopher JOhio State University (author)
  • Churchhouse, Claire (author)
  • de la Chapelle, AlbertOhio State University (author)
  • Klein, Daryl EYale University (author)
  • Nilsson, BjörnLund University,Lunds universitet,Avdelningen för hematologi och transfusionsmedicin,Institutionen för laboratoriemedicin,Medicinska fakulteten,Hematogenomics,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Hematology and Transfusion Medicine,Department of Laboratory Medicine,Faculty of Medicine,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Massachusetts Institute of Technology(Swepub:lu)klin-bni (author)
  • Wilson, Peter W F (author)
  • Cho, Kelly (author)
  • Pyarajan, Saiju (author)
  • Gaziano, J Michael (author)
  • Samani, Nilesh JGlenfield Hospital (author)
  • Regev, Aviv (author)
  • Palotie, AarnoUniversity of Helsinki(Swepub:lu)med-aop (author)
  • Neale, Benjamin MMassachusetts Institute of Technology (author)
  • Dick, John EUniversity of Toronto (author)
  • Natarajan, PradeepBroad Institute (author)
  • O'Donnell, Christopher JBrigham and Women's Hospital / Harvard Medical School (author)
  • Daly, Mark JUniversity of Helsinki(Swepub:lu)med-mkd (author)
  • Milyavsky, MichaelTel-Aviv University (author)
  • Kathiresan, SekarMassachusetts General Hospital (author)
  • Sankaran, Vijay GDana-Farber Cancer Institute (author)
  • Harvard Medical SchoolMassachusetts Institute of Technology (creator_code:org_t)
  • FinnGen

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  • In:Nature: Springer Science and Business Media LLC586:7831, s. 769-7750028-08361476-4687

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