Abstract IA002: Inherited DNA repair defects and premature aging

Abstract

Abstract Fanconi anemia (FA), a DNA repair disorder, is the most frequently inherited bone marrow failure (BMF) syndrome. Patients with FA suffer from early childhood onset of BMF, developmental abnormalities, and heightened susceptibility to solid tumors. FA patients also have a strong predisposition to myelo- dysplastic syndrome (MDS) and acute myeloid leukemia (AML). FA is caused by biallelic mutations in one of 23 FANC genes, whose protein products cooperate in the FA/BRCA DNA repair pathway and regulate cellular resistance to DNA cross-linking agents. Because of their underlying DNA repair defect, FA cells exhibit chromosomal instability and hypersensitivity to genotoxic DNA cross-linking agents, such as mitomycin C (MMC). FA bone marrow (BM) HSPCs are also hypersensitive to oxidative stress and inflammatory cytokines. FA patients and FA cells exhibit many features of Premature Aging. FA patients develop BMF because of HSPC exhaustion. Progressive age-related attrition is observed in CD34+ cell content in FA patients. Additionally, FA patients and FA mice exhibit HSPC functional defects. BMF in FA results from accumulation of DNA damage in HSPCs caused by endogenous cross-linking agents or physiological stress. In response to genotoxic stress, FA HSPCs hyperactivate growth-suppressive pathways, such as the p53 pathway (Ceccaldi et al, Cell Stem Cell, 2012) and the transforming growth factor (TGF-b) pathway (Zhang et al, Cell Stem Cell, 2016), further contributing to BMF. The molecular pathways in FA HSPCs leading to BMF and MDS/AML remain unknown. Although primary HSPCs from BM of FA patients are a useful model system, studying these cells is challenging because of their heterogeneity and low numbers. Sub-populations of HSPCs with heterogeneous transcriptional profiles may co-exist in the BM of FA patients. These subpopulations may include (1) stressed HSPCs sustaining hematopoiesis, (2) HSPCs committed to apoptosis resulting from accumulation of unrepaired DNA damage, and (3) premalignant/malignant cells that eventually lead to clinically detectable MDS or AML. Recently, in order to identify determinants of BMF, we performed single-cell transcriptome profiling of primary HSPCs from FA patients (Rodriguez et al, Cell Stem Cell, 2020). In addition to overexpression of p53 and TGF-b pathway genes, we identified high levels of MYC expression. We correspondingly observed coexistence of distinct HSPC subpopulations expressing high levels of TP53 or MYC in FA bone marrow (BM). MYC-high HSPCs showed significant downregulation of cell adhesion genes, consistent with enhanced egress of FA HSPCs from bone marrow to peripheral blood. We speculate that MYC overexpression impairs HSPC function in FA patients and contributes to exhaustion in FA bone marrow. In my seminar, I will describe the cellular and clinical manifestations of senescence and premature aging in FA patients. Specifically, FA patients exhibit the three major causes of cellular senescence including 1) replicative senescence 2) oncogene-induced senescence (OIS) and 3) stress-induced senescence. Citation Format: Alan D. D'Andrea. Inherited DNA repair defects and premature aging [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA002.