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调控HSP可影响遗传性MNP风险
2020-10-15 16:14

美国哈佛医学院波士顿儿童医院Vijay G. Sankaran研究组取得最新进展。他们发现遗传性骨髓增生性肿瘤风险影响造血干细胞(HSC)。这一研究成果于2020年10月14日发表在国际顶尖学术期刊《自然》上。

通过进行大规模的全基因组关联研究(3797例病例和1152977例对照),他们确定了17个MPN风险基因座(P <5.0×10-8),其中7个以前未见报道。他们发现,骨髓增生性肿瘤(MPN)风险与不同谱系的几种造血特征之间存在共同的遗传结构。在HSC的染色质中,MPN风险变异丰富,并且MPN风险增加与白细胞和其他克隆性造血状态中端粒长度的增加有关。总的说来,MPN风险与HSC功能和自我更新有关。

他们使用基因映射来识别与MPN风险相关的HSC生物学调控子,并通过针对性的功能变异检测,显示CHEK2和GFI1B在改变HSC的功能以赋予疾病风险方面具有作用。总的来说,他们的研究结果发现,通过调节HSC功能揭示了遗传MPN风险的先前未曾发现的机制。

据了解,MPN是血液癌症,其特征是成熟髓细胞的过量产生,并由源于HSC中体细胞驱动突变获得。流行病学研究表明,MPN的大量遗传成分是已知的最高发癌症。但是,仅确定了数量有限的遗传风险基因座,导致获得MPN的潜在生物学机制仍不清楚。

附:英文原文

Title: Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells

Author: Erik L. Bao, Satish K. Nandakumar, Xiaotian Liao, Alexander G. Bick, Juha Karjalainen, Marcin Tabaka, Olga I. Gan, Aki S. Havulinna, Tuomo T. J. Kiiskinen, Caleb A. Lareau, Aitzkoa L. de Lapuente Portilla, Bo Li, Connor Emdin, Veryan Codd, Christopher P. Nelson, Christopher J. Walker, Claire Churchhouse, Albert de la Chapelle, Daryl E. Klein, Bjrn Nilsson, Peter W. F. Wilson, Kelly Cho, Saiju Pyarajan, J. Michael Gaziano, Nilesh J. Samani, Aviv Regev, Aarno Palotie, Benjamin M. Neale, John E. Dick, Pradeep Natarajan, Christopher J. ODonnell, Mark J. Daly, Michael Milyavsky, Sekar Kathiresan, Vijay G. Sankaran

Issue&Volume: 2020-10-14

Abstract: 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 × 108), 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.

DOI: 10.1038/s41586-020-2786-7

Source: https://www.nature.com/articles/s41586-020-2786-7

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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