Abstract 4398: TET2 accelerates clonal hematopoiesis in an age-dependent manner

Abstract Aging is a process of systemic deterioration and the most significant risk factor for cancers. Clonal hematopoiesis (CH) commonly occurs with aging and links to higher mortality, leukemia risk, and cardiovascular diseases. Age-related CH involves the abnormal clonal expansion of hematopoietic stem cells (HSCs) bearing somatic mutations in genes frequently mutated in leukemia, including genes encoding epigenetic regulators, such as the DNA demethylase TET2. While such mutations are known to alter the HSC epigenome, the mechanisms through which these mutations drive HSC self-renewal, myeloid transformation, and inflammatory response remain elusive. In this study, we hypothesize that aging and CH mutations cooperatively reshape the HSC transcriptomic landscape and enhancing HSC competitive advantage that facilitates clonal expansion. Recently, TET2-mutant CH in humans has been strongly associated with epigenetic age acceleration. Using single-cell multi-omic analyses and flow-cytometric phenotyping, we demonstrated, for the first time, that HSC aging processes at transcriptomic, epigenomic, and cellular levels are accelerated by Tet2 deficiency in mice, in an age-dependent manner. Tet2-deficient HSCs increase the HSC aging scores at an older age of greater than or equal to 16 months, but not at a young or mid-age, based on gene expression and chromatin accessibility at a single-cell resolution. This age acceleration was further validated by epigenetic clock analysis of DNA methylation mapping. Moreover, we found that Tet2 deficiency drives a significant expansion of HSCs, a cellular hallmark of HSC aging, in an age-dependent manner. Specifically, we observed increased expression of S100a6, Cdk6, Egr1 in Tet2-deficient HSCs from older mice, suggesting that Tet2 deficiency hijacks the HSC expansion strategy during HSC aging by enhanced self-renewal. We also observed that the differentially expressed genes between Tet2-deficient older HSCs and control older HSCs are associated with open chromatin accessibility. Many of these genes are enriched in the targets of specific transcription factors (TFs), such as Egr1, Creb1, Stat family and Hoxb8. These target genes play critical roles in inflammatory pathways and HSC functions. In conclusion, our findings reveal that Tet2 deficiency significantly contributes to the acceleration of HSC aging, and hijacks the HSC expansion strategy (e.g., self-renewal) during HSC aging, which exacerbates age-related clonal hematopoiesis. By elucidating the transcriptomic and epigenomic alterations in Tet2-deficient HSCs, our study provides novel insights into how age and somatic mutations collaborate to promote the pathogenesis of age-related hematological diseases. These discoveries not only enhance our understanding of HSC aging mechanisms but also offer potential biomarkers for early detection and targets for therapeutic intervention in age-associated clonal disorders. Citation Format: Shilpita Karmakar, Yang Liu, Efthymios Motakis, Kaustav Sengupta, Travis Roeder, Kristina Mujica, Jennifer Trowbridge, Hideyuki Oguro, Sheng Li. TET2 accelerates clonal hematopoiesis in an age-dependent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4398.