Impact of IL-1 signaling on hematopoietic stem cell function and emergence of clonal hematopoiesis.

项目总结 这项建议长期目标是确定促进小鼠克隆性造血的机制(S 不定电势(芯片)。CHIP是心血管疾病、髓系血液病的危险因素 恶性和全因致死。CHIP被认为来自突变的造血干细胞(HSC) 携带癌基因突变，赋予细胞更强的适合性，导致突变的扩大 克隆人。携带芯片相关突变的罕见造血克隆在健康人群中几乎无处不在 个人。然而，CHIP主要局限于老年人或有吸烟史、化疗史的患者。 或接受放射治疗。这表明生理扰动(S)是衰老和遗传毒素所特有的 暴露，如慢性炎症，是驱动芯片所必需的。 为了更好地了解芯片背后的机制，我们进行了老鼠研究，表明慢性 骨髓中IL-1的产生是衰老和暴露于放射或化疗的常见后果。我们的 初步数据显示，慢性IL-1激活与PU1诱导相关的细胞生长抑制程序 长期HSC(HSCLT)。值得注意的是，缺乏TET2的HSCLT未能在 IL-1暴露。沿着这些思路，我们的数据显示，增加缺乏TET2的克隆扩张需要 慢性IL-1。这些初步数据表明，突变型HSC的克隆性扩增是一种新的特征 依赖慢性炎症。 这里提出的研究将识别和表征分子和细胞机制，通过这些机制 以TET2缺乏症为模型，慢性IL-1促进突变型HSC克隆扩增。调查路线 将包括对暴露于IL-1和竞争性的正常和TET2缺陷的HSC的分子和细胞分析 移植试验评估慢性IL-1对正常和TET2缺陷HSC适合性的功能影响 并肩而行。最后，实验将评估IL-1阻断是否能恢复正常的HSC健康和 逆转或限制克隆扩张。总之，我们的研究可以为将芯片重新定义为 潜在可逆的体细胞进化过程，其中炎性的BM环境选择突变 HSC克隆。

PROJECT SUMMARY The long-term objective of this proposal is to identify mechanism(s) that promote clonal hematopoiesis of indeterminate potential (CHIP). CHIP is a risk factor for cardiovascular disease, myeloid hematological malignancy, and all-cause mortality. CHIP is thought to arise from mutant hematopoietic stem cells (HSC) carrying oncogenic mutations that endow the cells with increased fitness, leading to expansion of the mutant clone. Rare hematopoietic clones carrying CHIP-associated mutations are near-ubiquitous in healthy individuals. However, CHIP is largely confined in older individuals or patients with a history of smoking, chemo- or radiotherapy exposure. This suggests that physiological perturbation(s) unique to aging and genotoxin exposure, such as chronic inflammation, are required to drive CHIP. To better understand the mechanism underlying CHIP, we have conducted mouse studies that indicate chronic IL-1 production in the BM is a common consequence of aging and exposure to radiation or chemotherapy. Our preliminary data show that chronic IL-1 activates a cell growth arrest program associated with PU.1 induction in long-term HSC (HSCLT). Strikingly, Tet2-deficient HSCLT fail to fully activate this growth arrest program during IL-1 exposure. Along these lines, our data show that increased Tet2-deficient clonal expansion requires chronic IL-1. These preliminary data suggest that clonal expansion of mutant HSC is an emergent feature dependent on chronic inflammation. The studies proposed here will identify and characterize the molecular and cellular mechanisms by which chronic IL-1 promotes mutant HSC clonal expansion, using Tet2-deficiency as a model. Lines of investigation will include molecular and cellular analyses of normal and Tet2-deficient HSC exposed to IL-1, and competitive transplant assays to assess the functional impact of chronic IL-1 on normal and Tet2-deficient HSC fitness side-by-side. Lastly, experiments will assess whether IL-1 blockade can restore normal HSC fitness and reverse or limit clonal expansion. Altogether, our investigations could provide a basis for redefining CHIP as a potentially reversible process of somatic evolution in which an inflammatory BM environment selects for mutant HSC clones.