Ionizing radiation induced hematological malignancies

电离辐射诱发的血液系统恶性肿瘤

• 批准号: 10722863
• 负责人: DAOHONG ZHOU
• 金额: $ 7.81万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10722863
• 关键词: Ionizing; radiation; induced; hematological; malignancies

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.

项目概要/摘要 电离辐射 (IR) 是一种公认​​的人类致癌物，接触 IR 与 诱导血液恶性肿瘤（HMs）和实体癌。 IR 诱发的患病率和发生率 HMs 包括治疗相关的骨髓增生异常综合征和急性髓性白血病 (tMDS/AML) 上升是因为接受放疗和/或化疗的癌症患者的生存率得到改善， 更多患者接受 CT 扫描进行医学诊断，尤其是儿童。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 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，两者都没有 IR 诱导 HMs 的机制尚未阐明，也尚未制定策略 有效防止IR对HMs的诱导。这些差距将在本申请中得到解决。具体来说， 我们计划检验一个最初的假设，即 IR 后造血干细胞 (HSC) 适应性的恢复 通过使用可以选择性杀死衰老细胞的衰老药物选择性地消耗衰老的 HSC （SC）有潜力被开发为一种新的基于机制的策略来预防 IR 诱导的 HM。这是因为新的证据表明，IR 诱导 HMs 的部分原因是减少 促进 HSC 的克隆性造血和已有的和 IR 诱导的 HSC 的扩增 致癌突变以获得优势并积累额外的突变以进行转化。这 我们最近的研究结果也支持了这一假设，表明 HSC 衰老的诱导是 小鼠暴露于亚致死剂量的全身后 HSC 适应性下降的主要原因 辐照（TBI）。通过遗传或药理学选择性消耗 SC 并使衰老的 HSC 恢复活力 TBI 诱导的过早衰老的 HSC 和老年小鼠中正常老化的 HSC 可能部分是由于 刺激正常 HSC 的扩张。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) 定量和定性确定正常 HSC 池 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 的消耗可以刺激正常 HSC 的扩张，减少 IR 诱导的 基因组不稳定，并抑制突变 HSC 的扩增； 3) 确定是否是遗传因素或 TBI 后衰老 HSC 的药物消耗可防止 HM 的发展。我们提出的 研究将通过确定新目标（例如 SC）和 用于化学预防的新型药物（例如抗衰老药物）。此外，HSC 衰老也发生在 化疗和年龄。使用衰老药物选择性清除衰老的 HSC 可能具有广泛的应用前景 减少癌症患者化疗引起的继发性 HMs 的应用，以及从头开始 通过改善 HSC 的健康状况，实现老年人体内的 HM。

项目成果

The Wave2 scaffold Hem-1 is required for transition of fetal liver hematopoiesis to bone marrow.

• DOI: 10.1038/s41467-018-04716-5
• 发表时间: 2018-06-18
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Shao L;Chang J;Feng W;Wang X;Williamson EA;Li Y;Schajnovitz A;Scadden D;Mortensen LJ;Lin CP;Li L;Paulson A;Downing J;Zhou D;Hromas RA
• 通讯作者: Hromas RA

Targeting anti-apoptotic BCL-2 family proteins for cancer treatment.

• DOI: 10.4155/fmc-2020-0004
• 发表时间: 2020-02
• 期刊: Future medicinal chemistry
• 影响因子: 4.2
• 作者: Xuan Zhang;Xingui Liu;Daohong Zhou;Guangrong Zheng

Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-XL.

• DOI: 10.1039/c9cc07217a
• 发表时间: 2019-11
• 期刊: Chemical communications
• 影响因子: 4.9
• 作者: Xuan Zhang;Dinesh Thummuri;Yonghan He;Xingui Liu;Peiyi Zhang;Daohong Zhou;Guangrong Zheng

Discovery of PROTAC BCL-XL degraders as potent anticancer agents with low on-target platelet toxicity.

• DOI: 10.1016/j.ejmech.2020.112186
• 发表时间: 2020-02
• 期刊: European journal of medicinal chemistry
• 影响因子: 6.7
• 作者: Xuan Zhang;Dinesh Thummuri;Xingui Liu;Wanyi Hu;Peiyi Zhang;Sajid Khan;Yaxia Yuan;Daohong Zhou;Guangrong Zheng