Selective pressures from inherited variation impacting myeloproliferative neoplasm initiation

遗传变异的选择性压力影响骨髓增生性肿瘤的发生

• 批准号: 10651876
• 负责人: Vijay Ganesh Sankaran
• 金额: $ 49.78万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651876
• 关键词: Address; Alleles; CHEK2 gene; Cells; Coupling; DNA Sequence Alteration; Data; Development; Disease; Downstream Enhancer; Enhancers; GFI1B gene; Genes; Genetic; Genetic Variation; Grant; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Heritability; Human; Individual; Inherited; Laboratories; Libraries; Malignant Neoplasms; Modeling; Mus; Myeloproliferative disease; Predisposition; Process; Property; Regulatory Element; Risk; Role; Somatic Mutation; Untranslated RNA; Variant; Work; cancer risk; disorder risk; epidemiology study; follow-up; genetic association; genome editing; genome sequencing; genome wide association study; genome-wide; hematopoietic stem cell self-renewal; innovation; insight; loss of function; mouse model; polygenic risk score; pressure; risk variant; tumorigenesis; whole genome

Project Summary/ Abstract While substantial progress has been made to delineate the somatic mutations that drive myeloproliferative neoplasms (MPNs), epidemiologic studies demonstrate a significant heritable risk for disease acquisition. We have recently conducted the largest genome-wide association study of MPNs to define inherited risk variants that promote the acquisition of this disease. Our initial analyses suggest a role for modulation of HSC self- renewal and function by these inherited risk variants. However, we lack a complete mechanistic understanding of how the selective pressures that arise from these inherited variants can promote MPN acquisition. Here, in this R01, we specifically want to understand how inherited risk variants can provide selective pressures to enable MPN initiation. In the first aim of this grant, we seek to use rigorous mouse models to define how a variant- containing HSC-selective enhancer of Gfi1b can promote MPN acquisition. We will study how this enhancer plays a role in native hematopoiesis to promote MPN initiation, as well as how this enhancer can cooperate with somatic mutations in this process. In the second aim of this grant, we seek to understand how loss-of-function of CHEK2 can promote MPN acquisition and clonal hematopoiesis by coupling genome editing of primary human hematopoietic stem/ progenitor cells and whole genome sequencing to assess how such germline genetic mutations can promote oncogenesis. Finally, in the third aim, we seek to more holistically define how variant- harboring regulatory elements and target genes may play a role in HSC self-renewal and function through the use of a multiplexed guide-swap Cas9 genome editing approach in primary human hematopoietic stem and progenitor cells. Collectively, the studies we propose in this grant will provide new insights into how inherited risk variants can provide selection pressures that enable MPNs to arise.

项目摘要/摘要 尽管已经取得了很大的进步来描述驱动骨髓增生性的躯体突变 肿瘤（MPN），流行病学研究表明，疾病的遗传风险很大。我们 最近已经进行了最大的全基因组关联研究MPN，以定义遗传的风险变体 这促进了这种疾病的收购。我们的初步分析表明，调节HSC自我的作用 这些继承的风险变体的更新和功能。但是，我们缺乏完整的机械理解 从这些继承的变体产生的选择性压力如何促进MPN的获取。在此处 这是R01，我们特别想了解继承的风险变体如何提供选择性的压力以启用 MPN启动。在这笔赠款的第一个目的中，我们试图使用严格的鼠标模型来定义变体的方式 - 含有GFI1B的HSC选择性增强子可以促进MPN获取。我们将研究这个增强器 在本地造血中发挥作用，以促进MPN的启动，以及该增强剂如何与 在此过程中的体细胞突变。在这笔赠款的第二个目标中，我们试图了解功能丧失 CHEK2可以通过耦合原代人的基因组编辑来促进MPN的获取和克隆造血 造血干/祖细胞和整个基因组测序，以评估这种种系遗传如何 突变会促进肿瘤发生。最后，在第三个目标中，我们寻求更全面地确定变体的方式 - 携带监管元素和靶基因可能在HSC自我更新中发挥作用，并通过 在原发性人类造血茎中使用多路复用指南CAS9 CAS9基因组编辑方法 祖细胞。总的来说，我们在这笔赠款中提出的研究将提供有关继承风险如何的新见解 变体可以提供使MPN出现的选择压力。