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Inherited myeloprol...
Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells
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- Bao, Erik L (author)
- Harvard Medical School
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- Nandakumar, Satish K (author)
- Harvard Medical School
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- Liao, Xiaotian (author)
- Harvard Medical School
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- Bick, Alexander G (author)
- Massachusetts Institute of Technology
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- Karjalainen, Juha (author)
- University of Helsinki
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- Tabaka, Marcin (author)
- Massachusetts Institute of Technology
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- Gan, Olga I (author)
- University of Toronto
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- Havulinna, Aki S (author)
- University of Helsinki
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- Kiiskinen, Tuomo T J (author)
- University of Helsinki
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- Lareau, Caleb A (author)
- Harvard Medical School
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- de Lapuente Portilla, Aitzkoa L (author)
- Lund 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
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- Li, Bo (author)
- Massachusetts Institute of Technology,Massachusetts General Hospital
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- Emdin, Connor (author)
- Massachusetts Institute of Technology
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- Codd, Veryan (author)
- Glenfield Hospital
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- Nelson, Christopher P (author)
- Glenfield Hospital
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- Walker, Christopher J (author)
- Ohio State University
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Churchhouse, Claire (author)
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- de la Chapelle, Albert (author)
- Ohio State University
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- Klein, Daryl E (author)
- Yale University
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- Nilsson, Björn (author)
- Lund 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
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Wilson, Peter W F (author)
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Cho, Kelly (author)
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Pyarajan, Saiju (author)
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Gaziano, J Michael (author)
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- Samani, Nilesh J (author)
- Glenfield Hospital
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Regev, Aviv (author)
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- Palotie, Aarno (author)
- University of Helsinki
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- Neale, Benjamin M (author)
- Massachusetts Institute of Technology
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- Dick, John E (author)
- University of Toronto
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- Natarajan, Pradeep (author)
- Broad Institute
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- O'Donnell, Christopher J (author)
- Brigham and Women's Hospital / Harvard Medical School
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- Daly, Mark J (author)
- University of Helsinki
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- Milyavsky, Michael (author)
- Tel-Aviv University
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- Kathiresan, Sekar (author)
- Massachusetts General Hospital
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- Sankaran, Vijay G (author)
- Dana-Farber Cancer Institute
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(creator_code:org_t)
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- 2020-10-14
- 2020
- English 7 s.
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 586:7831, s. 769-775
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http://dx.doi.org/10...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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Nature
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- By the author/editor
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Bao, Erik L
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Nandakumar, Sati ...
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Liao, Xiaotian
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Bick, Alexander ...
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Karjalainen, Juh ...
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Tabaka, Marcin
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show more...
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Gan, Olga I
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Havulinna, Aki S
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Kiiskinen, Tuomo ...
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Lareau, Caleb A
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de Lapuente Port ...
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Li, Bo
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Emdin, Connor
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Codd, Veryan
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Nelson, Christop ...
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Walker, Christop ...
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Churchhouse, Cla ...
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de la Chapelle, ...
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Klein, Daryl E
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Nilsson, Björn
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Wilson, Peter W ...
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Cho, Kelly
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Pyarajan, Saiju
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Gaziano, J Micha ...
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Samani, Nilesh J
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Regev, Aviv
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Palotie, Aarno
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Neale, Benjamin ...
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Dick, John E
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Natarajan, Prade ...
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O'Donnell, Chris ...
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Daly, Mark J
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Milyavsky, Micha ...
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Kathiresan, Seka ...
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Sankaran, Vijay ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Hematology
- Articles in the publication
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Nature
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Lund University