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Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells
Nature ( IF 64.8 ) Pub Date : 2020-10-14 , DOI: 10.1038/s41586-020-2786-7
Erik L Bao 1, 2, 3, 4 , Satish K Nandakumar 1, 2, 3 , Xiaotian Liao 1, 2, 3 , Alexander G Bick 3, 5, 6, 7, 8 , Juha Karjalainen 9 , Marcin Tabaka 3 , Olga I Gan 10, 11 , Aki S Havulinna 9 , Tuomo T J Kiiskinen 9 , Caleb A Lareau 1, 2, 3, 12 , Aitzkoa L de Lapuente Portilla 13 , Bo Li 3, 14 , Connor Emdin 3, 5 , Veryan Codd 15, 16 , Christopher P Nelson 15, 16 , Christopher J Walker 17 , Claire Churchhouse 3 , Albert de la Chapelle 17 , Daryl E Klein 18 , Björn Nilsson 3, 13 , Peter W F Wilson 19, 20 , Kelly Cho 21, 22 , Saiju Pyarajan 21 , J Michael Gaziano 21, 22 , Nilesh J Samani 15, 16 , , , Aviv Regev 3, 23, 24 , Aarno Palotie 3, 9 , Benjamin M Neale 3 , John E Dick 10, 11 , Pradeep Natarajan 3, 5, 25 , Christopher J O'Donnell 7, 22 , Mark J Daly 3, 9 , Michael Milyavsky 26 , Sekar Kathiresan 3, 5, 27 , Vijay G Sankaran 1, 2, 3, 28
Affiliation  

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.

中文翻译:

遗传性骨髓增生性肿瘤风险影响造血干细胞

骨髓增生性肿瘤 (MPN) 是一种血癌,其特征是成熟骨髓细胞的过度产生,并且由造血干细胞 (HSC) 中获得体细胞驱动突变引起。流行病学研究表明,MPN 中有一个重要的可遗传成分,它是已知的癌症中最常见的成分之一 1 。然而,仅确定了有限数量的遗传风险位点,并且导致获得 MPN 的潜在生物学机制仍不清楚。在这里,通过进行大规模全基因组关联研究(3,797 个病例和 1,152,977 个对照),我们确定了 17 个 MPN 风险位点 ( P < 5.0 × 10 -8 ),其中 7 个以前从未报道过。我们发现 MPN 风险和来自不同谱系的几种造血特征之间存在共同的遗传结构;HSC 的可及染色质内存在 MPN 风险变异的富集;MPN 风险增加与白细胞和其他克隆造血状态中较长的端粒长度相关,这共同表明 MPN 风险与 HSC 的功能和自我更新相关。我们使用基因图谱来识别与 MPN 风险相关的 HSC 生物学调节因子,并通过靶向变异功能测定表明 CHEK2 和 GFI1B 在改变 HSC 功能以赋予疾病风险方面发挥作用。总体而言,我们的结果揭示了一种以前未被认识到的通过调节 HSC 功能导致遗传性 MPN 风险的机制。一项全基因组关联研究确定了 17 个与骨髓增生性肿瘤 (MPN) 风险相关的基因位点,并表明造血干细胞功能的调节会增加 MPN 风险。
更新日期:2020-10-14
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