Mechanisms of marrow microenvironmental aging and their impact of progression of clonal hematopoiesis

项目摘要 造血细胞中的突变克隆，也称为克隆性造血（CH），存在于健康人中。 个体，并随着年龄的增长而扩大。尽管造血参数正常，但患有CH的个体 增加骨髓肿瘤、心血管风险和全因死亡率的风险。我们最近发现， 衰老的微环境有助于造血干细胞的命运选择。虽然克隆的存在 健康个体中的造血已经被广泛报道，并且其随着年龄增长的扩展已经确立， 衰老微环境是否改变了克隆动力学并有助于克隆选择， 骨髓增生异常综合征（MDS）的进展仍未探索。Sirtuin 6/SIRT 6是基因组的调节因子 和表观基因组稳定性。SIRT 6负责长寿物种更有效的DNA修复。此外 SIRT 6在抑制反转录转座子表达中起关键作用，表明反转录转座子活性 直接导致缺乏SIRT 6的小鼠中的早老样表型，部分是通过激活先天性 免疫力核苷酸逆转录酶抑制剂（NRTI）作为HIV药物开发，抑制逆转录转座， 减少炎症，改善野生型小鼠的衰老生物标志物，并延长早衰小鼠的寿命 缺少SIRT 6。我们推测，衰老相关的逆转录转座子去阻遏促进了前- 特异性造血干细胞支持性小生境群体（骨髓巨噬细胞）的炎症变化 和多能基质细胞），其驱动向骨髓肿瘤的克隆进展。为了验证这个假设， 使用克隆造血的相关模型，我们将检查1）白血病前突变是否形成克隆 在老年微环境中更容易发展为MDS， 受体小鼠; 2）SIRT 6在关键微环境群体中的过表达减缓了小鼠的免疫反应速率。 微环境和造血老化、克隆扩增和向MDS的进展; 3）抑制LINE 1 逆转录酶抑制剂（NRTI）的逆转录转座减缓了克隆扩增， 发现克隆造血进展的新微环境调节剂的机制。

Project Abstract Mutated clones in hematopoietic cells, also known as clonal hematopoiesis (CH) are present in healthy individuals and expand with aging. In spite of normal hematopoietic parameters, individuals with CH have increased risk of myeloid neoplasms, cardiovascular risk and all-cause mortality. We recently showed that the aged microenvironment contributes to hematopoietic stem cell fate choices. While the presence of clonal hematopoiesis in healthy individuals has been widely reported, and its expansion with aging is established, whether the aging microenvironment modifies clonal dynamics and contributes to clonal selection leading to progression to myelodysplastic syndromes (MDS) remains unexplored. Sirtuin6/SIRT6 is a regulator of genome and epigenome stability. SIRT6 is responsible for more efficient DNA repair in long-lived species. Moreover SIRT6 plays a critical role in suppressing retrotransposon expression, demonstrating that retrotransposon activity directly contributes to the progeroid phenotype in mice lacking SIRT6, in part through activation of innate immunity. Nucleotide reverse transcriptase inhibitors (NRTIs) developed as HIV drugs, inhibit retrotransposition, reduce inflammation, improve aging biomarkers in wild type mice, and extend the lifespan of progeroid mice lacking SIRT6. We hypothesize that aging-associated de-repression of retrotransposons promotes pro- inflammatory changes of specific hematopoietic stem cell-supportive niche populations (marrow macrophages and multipotent stromal cells) which drive clonal progression to myeloid neoplasms. To test this hypothesis, using relevant models of clonal hematopoiesis we will examine whether 1) pre-leukemic mutations form clones and progress to MDS more readily in the aged microenvironment by transplanting them into young versus aged recipient mice; 2) SIRT6 overexpression in key microenvironmental populations slows the rate of microenvironmental and hematopoietic aging, clonal expansion and progression to MDS; 3) repressing LINE1 retrotranspositions with inhibitors of reverse transcriptases (NRTIs) slows clonal expansion and provides a mechanism to discover novel microenvironmental regulators of clonal hematopoiesis progression.