Journal Article

Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells

Tabaka, Marcin, Samani, Nilesh J., Walker, Christopher J., Liao, Xiaotian, Bao, Erik L., Churchhouse, Claire, Nilsson, Björn, Natarajan, Pradeep, Wilson, Peter W. F., Emdin, Connor, Nandakumar, Satish K., Bick, Alexander G., Gan, Olga I., Nelson, Christopher P., Havulinna, Aki S., Karjalainen, Juha, Codd, Veryan, Milyavsky, Michael, Cho, Kelly, Dick, John E., Sankaran, Vijay G., Neale, Benjamin M., Regev, Aviv, Daly, Mark J., Palotie, Aarno, Lareau, Caleb A., de Lapuente Portilla, Aitzkoa L., Pyarajan, Saiju, Li, Bo, Gaziano, J. Michael, Kathiresan, Sekar, de la Chapelle, Albert, Klein, Daryl E., O’Donnell, Christopher J., Kiiskinen, Tuomo T. J.

2020

Overview

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 cancers 1 . 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. A genome-wide association study identifies 17 genetic loci that are associated with the risk of myeloproliferative neoplasms (MPNs), and shows that the modulation of haematopoietic stem cell function drives MPN risk.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 42 / 45/100 / 45/41 / 45/43 / 631/136/232 / 631/208/205/2138 / 692/699/1541/1990/2331 / 692/699/1541/1990/283/1897 / Analysis / Basic Medicine / Blood / Blood cancer / Cancer / Cell and Molecular Biology / Cell Lineage - genetics / Cell Self Renewal / Cell- och molekylärbiologi / Checkpoint Kinase 2 - genetics / Chromatin / Clinical Medicine / Diagnosis / Epidemiology / Female / Gene mapping / Genetic aspects / Genetic Predisposition to Disease - genetics / Genome-wide association studies / Genomes / Haplotypes / Health risk assessment / Health risks / Hematologi / Hematological diseases / Hematology / Hematopoietic stem cells / Hematopoietic Stem Cells - pathology / Humanities and Social Sciences / Humans / Klinisk medicin / Leukocytes / Leukocytes - pathology / Loci / Male / Medical and Health Sciences / Medicin och hälsovetenskap / Medicinska och farmaceutiska grundvetenskaper / Modulators / multidisciplinary / Mutation / Myeloid cells / Myeloproliferative disorders / Myeloproliferative Disorders - genetics / Myeloproliferative Disorders - pathology / Neoplasms / Neoplasms - genetics / Neoplasms - pathology / Population / Proto-Oncogene Proteins - genetics / Repressor Proteins - genetics / Risk / Risk factors / Science / Science (multidisciplinary) / Stem cells / Telomere Homeostasis / Telomeres / Tumors