Role of therapy-related clonal hematopoiesis in anthracycline-induced cardiotoxicity

总结 造血系统内驱动基因中体细胞DNA突变的积累可以提供一种新的治疗方法。 突变细胞的适应性优势，从而允许其克隆扩增。这个过程被称为克隆 造血，并导致一种情况，其中一个人的血细胞的相当大的一部分被取代， 带有驱动基因突变的克隆。先前在人类中的大外显子组测序研究已经表明， 这些体细胞突变在衰老过程中积累， 死亡此外，最近的实验研究支持了克隆造血因果地促进 心血管疾病（CVD）。最近，遗传毒性应激，如放射或化疗， 已经显示出促进癌症患者的造血克隆扩增。与年龄相关的无性系相比 主要由表观遗传调节因子如DNMT 3A和TET 2的突变介导的造血， 先前暴露于细胞毒性治疗导致的克隆性造血与高 TP 53和PPM 1D的突变频率。TP 53和PPM 1D突变体的克隆选择/扩增 克隆的癌症治疗可能会增加心血管疾病的风险，并解决这一临床相关 问题是目前建议的主要目的。 事实上， 在过去十年中， 癌症幸存者已经成长，因此，幸存者护理方法发生了范式转变， 专注于最大限度地提高非癌症相关的结果，如CVD。因此，存在未满足的需求， 了解癌症治疗相关的克隆造血和CVD之间的潜在联系。因此， 研究旨在检查治疗相关的克隆性造血与 化疗相关性心肌病作为概念验证，我将测试TP 53和 PPM 1D介导的克隆性造血促进蒽环类药物诱导的心肌病 复杂的动物模型

SUMMARY The accumulation of somatic DNA mutations in driver genes within the hematopoietic system can provide a fitness advantage to the mutant cell and thus allow for its clonal expansion. This process is referred to as clonal hematopoiesis and leads to a situation where a substantial fraction of an individual’s blood cells are replaced by clones with the driver gene mutation. Previous large exome sequencing studies in humans have shown that these somatic mutations accumulate during aging and are associated with a higher rate of cardiovascular-related deaths. Moreover, recent experimental studies support the idea that clonal hematopoiesis causally promotes cardiovascular disease (CVD). More recently, genotoxic stresses such as radiation or chemotherapy have also been shown to facilitate hematopoietic clonal expansion in cancer patients. Compared with age-related clonal hematopoiesis that is mediated primarily by mutations in epigenetic regulators such as DNMT3A and TET2, clonal hematopoiesis resulting from prior exposure to cytotoxic therapy is uniquely associated with high frequencies of mutations in TP53 and PPM1D. This clonal selection/expansion of TP53 and PPM1D mutant clones by cancer therapy may subsequently increase the risk of CVD, and addressing this clinically-relevant question represents the main objective of the current proposal. In fact, over the past decade, the number of cancer survivors has grown, thus there has been a paradigm shift in the approach to survivor care with a renewed focus on maximizing non-cancer-related outcomes, such as CVD. Therefore, there is an unmet need to understand the potential connection between cancer-therapy related clonal hematopoiesis and CVD. Thus, this study aims to examine whether a causal connection exists between therapy-related clonal hematopoiesis and chemotherapy-associated cardiomyopathy. As a proof-of-concept, I will test the hypothesis that TP53- and PPM1D-mediated clonal hematopoiesis contributes to anthracycline-induced cardiomyopathy using sophisticated animal models.