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

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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.