Interferon Signaling and the Differential Malignancy Spectrum of Down Syndrome

抽象的。 在NIH中被认可的包括(对生命周期中的共生情况进行调查以了解 唐氏综合症)项目，21三体(T21)是唐氏综合症的易感基因 (Ds)发展多样化的白血病，同时保护他们免受大多数实体恶性肿瘤的侵袭。然而， T21实现这些效应的机制还没有明确的定义。最近，芝加哥大学的成员 科罗拉多州癌症中心(UCCC)发现，T21持续激活干扰素(干扰素)反应 多种细胞类型，同时伴有与干扰素过度活动相一致的蛋白质组和代谢组变化 患有DS的人，这可以通过以下事实来解释：六个干扰素受体(IFNRs)中的四个编码在 21号染色体。重要的是，干扰素信号是一种强大的造血、免疫激活和肿瘤调节因子。 压制。因此，UCCC癌症中心支持补助金(CCSG)的这一补充资金的目标是 测试范式转换假设，即过度活跃的干扰素信号是差异的主要驱动因素 在DS患者中观察到的恶性谱系。更具体地说，我们假设过度活跃的干扰素 信号干扰造血，通过促进克隆性使个体倾向于白血病状态。 携带特定突变的细胞的扩张，同时也通过抑制恶性肿瘤的发展 肿瘤内在和外在机制的结合，如免疫激活。此外，我们假设 这种增加的干扰素信号增加了化疗的毒副作用，同时也影响了 嵌合抗原受体T细胞(CART)的功能。 在这一补充资金的资助下，UCCC将组建一支由UCCC成员组成的多学科协同团队 世卫组织将通过在人类和老鼠身上进行互补性研究来检验这些假说。由Key CCSG启用- 支持共享资源，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 DS患者及携带不同拷贝数IFNR基因簇的新型DS小鼠模型的研究 为了确定IFNR三倍体和高活性干扰素信号在以下方面的作用： ·造血室中白血病突变的克隆性扩展 ·儿童白血病化疗期间毒性增加 ·防止致癌物质和致癌基因驱动的实体恶性肿瘤 ·利用自然杀伤细胞和T细胞进行肿瘤监测 这些调查明确涉及包含项目的组成部分1(高风险-高回报基础科学)， 同时还利用与构成部分2相关的可用资源(DS的泛组学队列研究)。此外， 建议的研究完全属于家长奖的范围，尤其是NCI，更广泛地说，通过 研究可能导致癌症预防、诊断和治疗的新策略的机制。

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.