Genetic predisposition to myeloproliferative neoplasms implicates hematopoietic stem cell biology
Genetic predisposition to myeloproliferative neoplasms implicates hematopoietic stem cell biology
Myeloproliferative neoplasms (MPNs) are blood cancers characterized by excessive production of mature myeloid cells that result from the acquisition of somatic driver mutations in hematopoietic stem cells (HSCs)1. While substantial progress has been made to define the causal somatic mutation profile for MPNs2, epidemiologic studies indicate a significant heritable component for the disease that is among the highest known for all cancers3. However, only a limited set of genetic risk loci have been identified, and the underlying biological mechanisms leading to MPN acquisition remain unexplained. Here, to define the inherited risk profile, we conducted the largest genome-wide association study of MPNs to date (978,913 individuals with 3,224 cases) and identified 14 genome-wide significant loci, as well as a polygenic signature that increases the odds for disease acquisition by nearly 3-fold between the top and median deciles. Interestingly, we find a shared genetic architecture between MPN risk and several hematopoietic traits spanning distinct lineages, as well as an association between increased MPN risk and longer leukocyte telomere length, collectively implicating HSC function and self-renewal. Strikingly, we find a significant enrichment for risk variants mapping to accessible chromatin in HSCs compared with other hematopoietic populations. Finally, gene mapping identifies modulators of HSC biology and targeted variant-to-function analyses suggest likely roles for CHEK2 and GFI1B in altering HSC function to confer disease risk. Overall, we demonstrate the power of human genetic studies to illuminate a previously unappreciated mechanism for MPN risk through modulation of HSC function.
Lareau Caleb A.、Emdin Connor、Codd Veryan、Nandakumar Satish K.、Gan Olga I.、Kiiskinen Tuomo、Nelson Christopher P.、Milyavsky Michael、Kathiresan Sekar、Wilson Peter W.F.、Gaziano J. Michael、Dick John E.、Daly Mark J.、Regev Aviv、Li Bo、Million Veteran Program、O?ˉDonnell Christopher J.、Neale Benjamin M.、23andMe Research Team、Karjalainen Juha、Tabaka Marcin、Samani Nilesh J.、Churchhouse Claire、Sankaran Vijay G.、Natarajan Pradeep、Palotie Aarno、de Lapuente Portilla Aitzkoa L.、Bick Alexander、Cho Kelly、Pyarajan Saiju、Bao Erik L.、Nilsson Bj?rn、Havulinna Aki、Liao Xiaotian
Division of Hematology/Oncology, Boston Children?ˉs Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School Boston||Broad Institute of MIT and Harvard||Program in Biological and Biomedical Sciences, Harvard Medical SchoolBroad Institute of MIT and Harvard||Center for Genomic Medicine, Massachusetts General HospitalDepartment of Cardiovascular Sciences and NIHR Leicester Biomedical Centre, University of LeicesterDivision of Hematology/Oncology, Boston Children?ˉs Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School Boston||Broad Institute of MIT and HarvardPrincess Margaret Cancer Centre, University Health Network||Department of Molecular Genetics, University of TorontoInstitute for Molecular Medicine FinlandDepartment of Cardiovascular Sciences and NIHR Leicester Biomedical Centre, University of LeicesterDepartment of Pathology, Sackler Faculty of Medicine, Tel-Aviv UniversityBroad Institute of MIT and Harvard||Center for Genomic Medicine, Massachusetts General HospitalAtlanta VA Medical Center||Emory Clinical Cardiovascular Research InstituteMassachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System||Department of Medicine, Brigham and Women?ˉs HospitalPrincess Margaret Cancer Centre, University Health Network||Department of Molecular Genetics, University of TorontoBroad Institute of MIT and Harvard||Institute for Molecular Medicine FinlandBroad Institute of MIT and HarvardBroad Institute of MIT and Harvard||Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical SchoolVA Boston Healthcare, Section of Cardiology and Department of Medicine||Department of Medicine, Brigham and Women?ˉs HospitalBroad Institute of MIT and Harvard23andMe, IncInstitute for Molecular Medicine FinlandBroad Institute of MIT and HarvardDepartment of Cardiovascular Sciences and NIHR Leicester Biomedical Centre, University of LeicesterBroad Institute of MIT and HarvardDivision of Hematology/Oncology, Boston Children?ˉs Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School Boston||Broad Institute of MIT and Harvard||Harvard Stem Cell InstituteBroad Institute of MIT and Harvard||Center for Genomic Medicine, Massachusetts General Hospital||Cardiovascular Research Center, Massachusetts General HospitalBroad Institute of MIT and Harvard||Institute for Molecular Medicine FinlandHematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, SE-221 84 Lund UniversityBroad Institute of MIT and Harvard||Center for Genomic Medicine, Massachusetts General Hospital||VA Boston Healthcare, Section of Cardiology and Department of MedicineMassachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System||Department of Medicine, Brigham and Women?ˉs HospitalMassachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare SystemDivision of Hematology/Oncology, Boston Children?ˉs Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School Boston||Broad Institute of MIT and Harvard||Harvard-MIT Health Sciences and Technology, Harvard Medical SchoolBroad Institute of MIT and Harvard||Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, SE-221 84 Lund UniversityInstitute for Molecular Medicine FinlandDivision of Hematology/Oncology, Boston Children?ˉs Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School Boston||Broad Institute of MIT and Harvard
基础医学遗传学肿瘤学
Lareau Caleb A.,Emdin Connor,Codd Veryan,Nandakumar Satish K.,Gan Olga I.,Kiiskinen Tuomo,Nelson Christopher P.,Milyavsky Michael,Kathiresan Sekar,Wilson Peter W.F.,Gaziano J. Michael,Dick John E.,Daly Mark J.,Regev Aviv,Li Bo,Million Veteran Program,O?ˉDonnell Christopher J.,Neale Benjamin M.,23andMe Research Team,Karjalainen Juha,Tabaka Marcin,Samani Nilesh J.,Churchhouse Claire,Sankaran Vijay G.,Natarajan Pradeep,Palotie Aarno,de Lapuente Portilla Aitzkoa L.,Bick Alexander,Cho Kelly,Pyarajan Saiju,Bao Erik L.,Nilsson Bj?rn,Havulinna Aki,Liao Xiaotian.Genetic predisposition to myeloproliferative neoplasms implicates hematopoietic stem cell biology[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/790626.点此复制
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