Interferon Signaling and the Differential Malignancy Spectrum of Down Syndrome

干扰素信号转导和唐氏综合症的鉴别恶性肿瘤谱

• 批准号: 9933418
• 负责人: RICHARD D SCHULICK
• 金额: $ 46.16万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9933418
• 关键词: Address; Award; Basic Science; Cancer Center; Cancer Center Support Grant; Cancer Science; Carcinogens; Catchment Area; Cells; Childhood Leukemia; Chromosomes, Human, Pair 21; Clinical; Clonal Expansion; Cohort Studies; Colorado; Cytotoxic T-Lymphocytes; Development; Diagnosis; Down Syndrome; Funding; Gene Cluster; Goals; Hematopoiesis; Hematopoietic; Hospitals; Human; Hyperactive behavior; Individual; Interdisciplinary Study; Interferon Receptor; Interferons; Investigation; Lead; Longevity; Malignant Neoplasms; Mission; Mus; Mutation; Oncogenes; Parents; Pediatric Hospitals; Proteomics; Receptor Gene; Research; Resource Sharing; Resources; Role; Sampling; Signal Transduction; Solid; Testing; The University of Colorado Cancer Center; Toxic effect; Tumor Suppression; United States National Institutes of Health; Universities; cancer prevention; cell type; chemotherapy; chimeric antigen receptor T cells; falls; high reward; high risk; immune activation; leukemia; medical schools; member; metabolomics; mouse model; multidisciplinary; novel; novel strategies; receptor; response; side effect; tumor

ABSTRACT. As recognized in the NIH INCLUDE (Investigation of Co-occurring conditions across the Lifespan to Understand Down SyndromE) Project, it is well-established that trisomy 21 (T21) predisposes people with Down syndrome (DS) to develop diverse leukemias, while also protecting them from most solid malignancies. However, the mechanisms by which T21 achieves these effects are poorly defined. Recently, members of the University of Colorado Cancer Center (UCCC) discovered that T21 consistently activates the interferon (IFN) response in multiple cell types, concurrent with proteomic and metabolomic changes consistent with IFN hyperactivity in people with DS, which could be explained by the fact that four of the six IFN receptors (IFNRs) are encoded on chromosome 21. Importantly, IFN signaling is a potent regulator of hematopoiesis, immune activation, and tumor suppression. Therefore, the goal of this supplement to the UCCC Cancer Center Support Grant (CCSG) is to test the paradigm-shifting hypothesis that hyperactive IFN signaling is a main driver of the differential malignancy spectrum observed in people with DS. More specifically, we hypothesize that hyperactive IFN signaling disrupts hematopoiesis, predisposing individuals toward a leukemogenic state by promoting clonal expansion of cells bearing specific mutations, while also suppressing the development of malignancies through a combination of tumor-intrinsic and -extrinsic mechanisms, such as immune activation. Furthermore, we posit that increased IFN signaling augments the toxic side effects of chemotherapy, while also impacting on the function of chimeric antigen-receptor T cells (CARTs). Funded by this supplement, the UCCC will assemble a multidisciplinary and synergistic team of UCCC members who will test these hypotheses through complementary studies in humans and mice. Enabled by key CCSG- supported Shared Resources, this team will use human samples obtained from an ongoing pan-omics cohort study of people with DS and novel mouse models of DS carrying varying copy numbers of the IFNR gene cluster to define the role of IFNR triplication and hyperactive IFN signaling on: · Clonal expansion of leukemogenic mutations in the hematopoietic compartment · Increased toxicity during chemotherapy for pediatric leukemias · Protection from carcinogen- and oncogene-driven solid malignancies · Tumor surveillance by Natural Killer and T cells These investigations clearly address Component 1 of the INCLUDE project (high risk-high reward basic science), while also leveraging available resources related to Component 2 (pan-omics cohort study of DS). Furthermore, the research proposed falls well within the scope of the parent award in particular, and NCI more broadly, by investigating mechanisms that could lead to novel strategies for cancer prevention, diagnosis, and treatment.

摘要。 正如NIH INCLUDE（调查整个生命周期中的共发疾病，以了解 唐氏综合症）项目，它是公认的三体21（T21）的人容易患唐氏综合症 (DS)发展成不同的白血病，同时也保护他们免受大多数实体恶性肿瘤的侵害。但 T21实现这些效果的机制尚不清楚。最近，该大学的成员 科罗拉多癌症中心（UCCC）发现，T21在肿瘤细胞中持续激活干扰素（IFN）应答。 多种细胞类型，同时伴有与IFN高活性一致的蛋白质组学和代谢组学变化， DS患者，这可以解释为六种IFN受体（IFNRs）中的四种编码在 21号染色体。重要的是，IFN信号是造血、免疫激活和肿瘤的有效调节剂 镇压因此，UCCC癌症中心支持补助金（CCSG）的补充目标是 测试范式转换假设，即过度活跃的IFN信号是差异的主要驱动力， 在DS患者中观察到的恶性肿瘤谱。更具体地说，我们假设过度活跃的干扰素 信号传导破坏造血，通过促进克隆形成使个体倾向于白血病状态， 携带特定突变的细胞的扩增，同时还通过以下途径抑制恶性肿瘤的发展： 肿瘤内在和外在机制的组合，如免疫激活。此外，我们 IFN信号的增加会增加化疗的毒副作用，同时也会影响化疗的效果。 嵌合抗原受体T细胞（CART）的功能。 由这一补充资金，UCCC将组装一个多学科和协同UCCC成员的团队 他们将通过对人类和小鼠的补充研究来验证这些假设。由关键CCSG启用- 在共享资源的支持下，该团队将使用从正在进行的泛组学队列中获得的人类样本 对DS患者和携带不同拷贝数IFNR基因簇的新型DS小鼠模型的研究 确定IFNR三重化和过度活跃的IFN信号传导在以下方面的作用： ·造血区室中致白血病突变的克隆扩增 ·儿科白血病化疗期间毒性增加 ·防止致癌物和癌基因驱动的实体恶性肿瘤 ·自然杀伤细胞和T细胞的肿瘤监测 这些研究明确涉及INCLUDE项目的组成部分1（高风险-高回报基础科学）， 同时还利用与组件2（DS的泛组学队列研究）相关的可用资源。此外，委员会认为， 福尔斯提出的研究建议，特别是在国家癌症研究所的范围内，更广泛地说， 研究可能导致癌症预防，诊断和治疗新策略的机制。