Determinants of Myeloid Clonal Evolution

项目摘要 克隆性造血是随着年龄的增长而获得的，在某些情况下，在骨髓增生异常综合征和骨髓增生异常综合征发病之前， 和骨髓增生性疾病。然而，克隆植物进化背后的遗传驱动因素 造血和随后的疾病风险仍然知之甚少。该提案基于生成的 有证据表明，端粒长度，一种遗传和临床上可用的生物标志物， 孟德尔综合征中的造血我们还发现了明显的克隆造血的证据 这些突变似乎对发育不良和骨髓增生性表型有不同的易感性。在这 应用，我们将研究端粒长度在驱动克隆进化中的作用， 特征的队列，包括一个以巴尔的摩为基础的社区妇女队列， 美国子集。此外，我们还将研究一种新的克隆性造血的发生和流行情况。 端粒酶逆转录酶基因的突变似乎是对骨髓细胞的保护， 恶性肿瘤。这个K08赠款申请是由优秀的导师和在一个强大的翻译支持 约翰霍普金斯大学医学院的环境与详细的指导和培训计划， 侧重于遗传流行病学和计算生物学技能。这些知识有可能影响 目前与造血衰老、骨髓克隆性疾病风险相关的范例以及 特定疾病风险和进展。

PROJECT ABSTRACT Clonal hematopoiesis is acquired with aging, and in some cases, precedes the onset of both myelodysplastic and myeloproliferative disorders. However, the genetic drivers that underlie the evolution of clonal hematopoiesis and the subsequent disease risk remain poorly understood. This proposal builds on generated evidence showing that telomere length, a genetic and clinically available biomarker, predisposes to clonal hematopoiesis in Mendelian syndromes. We have also found evidence for distinct clonal hematopoiesis mutations that appear to differentially predispose to hypoplastic and myeloproliferative phenotypes. In this application, we will examine the role of telomere length in driving clonal evolution with aging in well- characterized cohorts including a Baltimore-based cohort of community-based women with a large African American subset. Additionally, we will also examine the onset and prevalence of a novel clonal hematopoiesis mutation in the telomerase reverse transcriptase gene that appears to be protective against myeloid malignancies. This K08 grant application is supported by outstanding mentors and in a strong translational environment at Johns Hopkins University School of Medicine with a detailed mentorship and training plan that focuses on genetic epidemiology and computational biology skills. The knowledge has the potential to impact current paradigms related to hematopoietic aging, myeloid clonal disease risk as well as novel biomarkers of specific disease risk and progression.