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)，在健康人群中存在 并随着年龄的增长而扩大。尽管有正常的造血参数，但慢性肝炎患者 增加患髓系肿瘤的风险、心血管风险和全因死亡率。我们最近展示了 衰老的微环境有助于造血干细胞的命运选择。而克隆人的存在 健康个体的造血功能已经被广泛报道，而且随着年龄的增长，它的扩张性也得到了证实， 衰老的微环境是否改变克隆动力学并有助于克隆选择导致 进展为骨髓增生异常综合征(MDS)仍未被探索。Sirtuin6/SIRT6是基因组的调节因子 和表观基因组稳定性。在长寿物种中，SIRT6负责更有效的DNA修复。更有甚者 SIRT6在抑制反转录转座子的表达中起关键作用，表明反转录转座子的活性 在缺乏SIRT6的小鼠中，直接对孕激素表型有贡献，部分是通过激活先天 豁免权。作为HIV药物开发的核苷酸逆转录酶抑制剂(NRTI)，抑制逆转座子， 减轻炎症，改善野生型小鼠衰老生物标志物，延长孕期小鼠寿命 缺少SIRT6。我们假设与衰老相关的反转录转座子的去抑制促进了前转座子的表达。 特定的造血干细胞支持生态位群体(骨髓巨噬细胞)的炎性变化 和多能基质细胞)，推动向髓系肿瘤的克隆性进展。为了检验这一假设， 利用克隆性造血的相关模型，我们将检查1)白血病前期突变是否形成克隆 通过将MDS移植到年轻人而不是老年人，更容易在老年微环境中进展为MDS 受体小鼠；2)SIRT6在关键微环境人群中的过度表达减缓了 微环境和造血老化、克隆性扩张和进展为MDS；3)抑制LINE1 逆转录酶抑制剂(NRTI)的逆转座可减缓克隆扩张，并提供 发现克隆性造血进展的新的微环境调节机制。

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.