Ionizing radiation induced hematological malignancies

电离辐射诱发的血液系统恶性肿瘤

• 批准号: 9216070
• 负责人: DAOHONG ZHOU
• 金额: $ 35.53万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2018-04-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9216070
• 关键词: Acute Myelocytic Leukemia; Address; Age; Aging; BCL2 gene; Biological Assay; Bone Marrow; Cancer Patient; Carcinogen exposure; Cell Aging; Cells; Chemoprevention; Child; Cytogenetic Analysis; Development; Diagnosis; Dose; Dysmyelopoietic Syndromes; Exposure to; Ganciclovir; Genetic; Genomic Instability; Goals; Hematologic Neoplasms; Hematopoiesis; Hematopoietic stem cells; Hodgkin Disease; Human; Incidence; Individual; Induction of Apoptosis; Ionizing radiation; Knock-in; Malignant Neoplasms; Medical; Mus; Mutate; Mutation; Non-Hodgkin' s Lymphoma; Oncogenic; Patients; Pharmaceutical Preparations; Pharmacology; Play; Prevalence; Prevention; Radiation therapy; Risk; Role; Scanning; Simplexvirus; Solid; Spectral Karyotyping; Testing; Thymic Lymphoma; Thymidine Kinase; Transgenic Mice; Transplantation; Whole-Body Irradiation; X-Ray Computed Tomography; aged; base; cancer survival; cellular targeting; chemotherapy; fitness; improved; improved functioning; inhibitor/antagonist; innovation; killings; leukemia; mouse model; novel; pediatric patients; premature; prevent; promoter; reconstitution; restoration; senescence

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.

项目摘要 /摘要 电离辐射（IR）是一种公认​​的人致癌，暴露于IR 诱导血液恶性肿瘤（HMS）和固体癌症。 IR诱导的患病率和发病率 HMS在内的HMS包括治疗相关的骨髓增生综合征和急性髓质白血病（TMDS/AML） 由于接受放疗和/或化学疗法治疗的癌症患者的存活而增加，并且 越来越多的患者接受CT扫描以进行医学诊断，尤其是在儿童中。目前，TMDS/AML帐户 大约15％至20％的MD和AML病例，代表了最严重的长期并发症 对于霍奇金和非霍奇金淋巴瘤和其他几种癌症的患者。不幸的是，都不是 具有阐明IR诱导HMS的机制，也没有制定策略 有效防止IR诱导HMS。这些差距将在此应用程序中解决。具体来说， 我们计划检验一个原始假设，即IR后造血干细胞（HSC）适应性的恢复 通过选择性耗尽衰老的HSC，用鼻溶液药物可以选择性地杀死衰老细胞 （SCS）有潜力作为一种基于机制的新型策略，以防止IR诱导 HMS。这是因为新证据表明，IR诱导HMS是部分归因于减少的 在HSC Fitness中，促进克隆造血和HSC的扩展，并具有先前和IR诱导的 致癌突变以获得优势并积累其他突变以进行转化。这 我们最近的发现也证明了HSC衰老的诱导是 暴露于全身的全身剂量后，主要负责小鼠HSC适应性的降低 辐照（TBI）。 SCS和衰老HSC的遗传或药理选择性耗竭已恢复活力 TBI和通常在老鼠中造成的年龄HSC诱导的过早衰老HSC可能部分是 刺激正常HSC的扩展。在此应用程序中，将追求三个特定目标来测试我们的 使用小鼠模型的假设：1）定量和定性地确定正常HSC的库 暴露于全剂量的TBI后保存； 2）确定遗传学还是药理 TBI后衰老HSC的耗竭可以刺激正常HSC的膨胀，减少IR诱导的 基因组不稳定性，并抑制突变的HSC的扩张； 3）确定遗传还是 TBI后衰老HSC的药理耗竭可防止HMS的发展。我们提出的 研究将通过识别新目标（例如SCS）和 用于化学预防的新型药物（例如鼻溶剂）。此外，HSC衰老也发生在 化学疗法并随着年龄的增长。用鼻溶剂的衰老HSC的选择性耗竭可能具有广泛的 在癌症患者和从头上减少化疗诱导的继发性HMS的应用 通过改善HSC的适应性，老年人的HMS。