Ionizing radiation induced hematological malignancies

项目总结/摘要 电离辐射（IR）是一种公认的人类致癌物，暴露于IR与 诱导血液恶性肿瘤（HM）和实体癌。胰岛素抵抗诱导的 HM包括治疗相关的骨髓增生异常综合征和急性骨髓性白血病（tMDS/AML）， 因为用放射疗法和/或化学疗法治疗的癌症患者的存活率提高， 更多的病人接受CT扫描以进行医学诊断，特别是儿童。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 霍奇金淋巴瘤和非霍奇金淋巴瘤以及其他几种癌症的患者。不幸的是， IR诱导HM的机制是否已经阐明，也没有开发出一种策略， 有效地防止由IR诱导HM。这些差距将在本申请中解决。具体地说， 我们计划验证一个原始假设，即IR后造血干细胞（HSC）适应性的恢复 通过使用可选择性杀死衰老细胞的衰老清除药物选择性消耗衰老HSC (SCs)有可能被开发为一种新的机制为基础的战略，以防止IR诱导的 嗯。这是因为新的证据表明，IR诱导HM部分归因于 在HSC适应性中，其促进具有预先存在的和IR诱导的HSC的克隆造血和扩增。 致癌突变以获得优势并积累额外的突变用于转化。这 我们最近的发现也支持了这一假设，表明HSC衰老的诱导是 主要负责在暴露于亚致死剂量的全身后小鼠中HSC适应性的降低 照射（TBI）。遗传选择性或非遗传选择性去除SC和衰老的HSC， 由TBI诱导的过早衰老的HSC和老年小鼠中正常衰老的HSC可能部分地通过 刺激正常HSC的扩增。在本申请中，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HSC库 在暴露于亚致死剂量的TBI后保存; 2）确定是否遗传或药理学 TBI后衰老HSC的耗竭可以刺激正常HSC的扩增，减少IR诱导的HSC增殖， 基因组不稳定性，并抑制突变的HSC的扩增;和3）确定是否遗传或 TBI后衰老HSC的药理学消耗防止HM的发展。我们提出的 研究将通过确定新的靶点（如SC）， 用于化学预防的新药剂（例如衰老清除药物）。此外，HSC衰老也发生在 化疗和年龄。用衰老清除药物选择性去除衰老HSC可能具有广泛的生物学效应。 应用于减少癌症患者中化疗诱导的继发性HM，以及新发 HMs在老年人中，通过改善HSC的适应性。

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.