Ionizing radiation induced hematological malignancies

项目摘要/摘要 电离辐射(IR)是一种公认的人类致癌物质，暴露于IR与 诱发血液系统恶性肿瘤(HMS)和实体癌。胰岛素抵抗的患病率和发病率 HMS包括治疗相关的骨髓增生异常综合征和急性髓系白血病(TMDS/AML) 上升是因为接受放疗和/或化疗的癌症患者的存活率提高了， 更多的患者接受CT扫描以进行医学诊断，特别是在儿童中。目前，TMDS/AML账户 约占所有MDS和AML病例的15%至20%，是最严重的长期并发症 适用于霍奇金和非霍奇金淋巴瘤以及其他几种癌症患者。不幸的是，两者都不是 IR诱导HMS的机制还没有阐明，也没有开发出一种策略来 有效防止IR诱导的HMS。这些差距将在本申请中得到解决。具体来说， 我们计划测试一个原始假设，即IR后造血干细胞(HSC)恢复健康 通过使用一种可以选择性杀死衰老细胞的衰老药物选择性地耗尽衰老的HSCs (SCS)有可能被开发为一种基于机制的预防IR诱导的新策略 英国皇家海军。这是因为新的证据表明，IR诱导HMS的部分原因是 在HSC适合性中，促进预先存在和IR诱导的HSC的克隆性造血和扩增 致癌突变以获得显性，并积累用于转化的额外突变。这 我们最近的发现也支持了这一假说，该发现表明，诱导HSC衰老是 暴露于亚致死剂量全身后小鼠HSC适合性下降的主要原因 照射(TBI)。基因或药物选择性地耗尽干细胞和衰老的造血干细胞恢复活力 脑创伤致衰老小鼠HSCs和正常衰老HSCs可能部分通过 刺激正常肝星状细胞的扩增。在此应用程序中，将追求三个具体目标来测试我们的 使用小鼠模型的假设：1)定量和定性地确定正常的HSC池 在暴露于亚致死剂量的TBI后保存；2)以确定遗传或药理学 脑损伤后衰竭的HSCs可刺激正常HSCs的扩张，减少IR诱导的HSCs 基因组的不稳定性，并抑制突变的造血干细胞的扩张；以及3)确定是遗传的还是 脑创伤后衰老的HSCs的药理耗竭可阻止HMS的发展。我们的建议 研究将通过确定新的目标(如SCs)和 用于化学预防的新型药物(如抗衰老药物)。此外，HSC衰老也发生在 化疗和随着年龄的增长。用抗衰老药物选择性去除衰老的HSCs可能有广泛的作用 减少癌症患者化疗引起的继发性HMS以及新生的应用 HMS在老年人中的应用，通过提高HSC的适合性来实现。

PROJECT SUMMARY / ABSTRACT Ionizing radiation (IR) is a well-established human carcinogen and exposure to IR is associated with the induction of hematological malignancies (HMs) and solid cancer. The prevalence and incidence of IR-induced HMs including therapy-related myelodysplastic syndrome and acute myelogenous leukemia (tMDS/AML) are rising because the survival of cancer patients treated with radiotherapy and/or chemotherapy improves and more patients receive CT scans for medical diagnosis particularly in children. Currently, tMDS/AML accounts for about 15% to 20% of all cases of MDS and AML and represents the most serious long-term complications for the patients with Hodgkin and non-Hodgkin lymphoma and several other cancers. Unfortunately, neither have the mechanisms by which IR induces HMs been elucidated nor has a strategy been developed to effectively prevent the induction of HMs by IR. These gaps will be addressed in this application. Specifically, we plan to test an original hypothesis that restoration of hematopoietic stem cell (HSC) fitness after IR via selective depletion of senescent HSCs with a senolytic drug that can selectively kill senescent cells (SCs) has the potential to be developed as a novel mechanism-based strategy to prevent IR-induced HMs. This is because new evidence suggests that induction of HMs by IR is in part attributable to a decrease in HSC fitness, which promotes clonal hematopoiesis and expansion of HSCs with preexisting and IR-induced oncogenic mutations to gain dominance and accumulate additional mutations for transformation. This hypothesis is also supported by our recent findings demonstrating that induction of HSC senescence was primarily responsible for the decrease of HSC fitness in mice after exposure to a sublethal dose of total body irradiation (TBI). Genetically or pharmacologically selective depletion of SCs and senescent HSCs rejuvenated the prematurely senescent HSCs induced by TBI and normally aged HSCs in old mice probably in part by stimulating the expansion of normal HSCs. In this application, three specific aims will be pursued to test our hypothesis using a mouse model: 1) to quantitatively and qualitatively determine the pool of normal HSCs preserved after exposure to a sublethal dose of TBI; 2) to determine whether genetic or pharmacological depletion of senescent HSCs after TBI can stimulate the expansion of normal HSCs, reduce IR-induced genomic instability, and suppress the expansion of mutated HSCs; and 3) to determine whether genetic or pharmacological depletion of senescent HSCs after TBI prevents the development of HMs. Our proposed studies will lead to a paradigm shift in prevention of IR-induced HMs by identifying new targets (e.g. SCs) and novel agents (e.g. senolytic drugs) for chemoprevention. Moreover, HSC senescence also occurs after chemotherapy and with age. Selective depletion of senescent HSCs with a senolytic drug may have broad applications for reduction of chemotherapy-induced secondary HMs in cancer patients, as well as de novo HMs in aged individuals, by improving the fitness of HSCs.