Abstract B027: Exploring how aging-associated changes in autophagy dictate the development of leukemic disease

Abstract

Abstract Old age leads to cellular maintenance decline, disrupting homeostasis and increasing disease risks, including cancer. Aging-related autophagy impairments contribute to harmful protein accumulation, reduced hematopoietic cell self-renewal, and impaired mitochondrial function. Autophagy plays a central role in maintaining cellular homeostasis and key cellular functions, such as cell death, cell cycle control, and differentiation. This research aims to investigate how aging-related microenvironmental changes influence Tet2 clonal hematopoiesis (CH) development, with a focus on understanding the roles of aging-associated autophagy changes. We hypothesize that the decline in cellular and tissue maintenance during aging, characterized by reduced autophagy function, contributes to changes in the bone marrow microenvironment. These changes, in turn, create a milieu conducive to the selection of oncogenic mutations. To test this hypothesis, we aimed to boost autophagy in older mice to investigate if it can mitigate oncogenesis, given that CH and cancers are less common in young individuals but prevalent in the elderly. 15-month-old mice were treated with a spermidine supplemented diet for 3 months, then LSK were transplanted with fluorescently tagged, CRISPR induced Tet2 mutations such that a small percent of HSPC bear mutations. We then monitored the competitive expansion of cells with Tet2. We found that old mice supplemented with spermidine show decreased Tet2 selection within the HSPC compartment similar to young (2mo) mice and compared to old mice on a control diet. We plan to test Tet2 competitive expansion in aged transgenic mice with high autophagy as well as the opposite experiment using transgenic young mice with decreased autophagy to further support our hypothesis. Our research emphasizes the role of autophagy in shaping the bone marrow microenvironment and influencing the development of CH. By examining how aging-associated changes in autophagy impact the selection of oncogenic mutations, our work contributes to a deeper understanding of the complex interplay between aging and cancer development. Our research has the potential to impact cancer treatment and the understanding of cancer evolution by shedding light on the mechanisms that drive oncogenic adaptation in the context of aging. Specifically, our findings suggest that enhancing autophagy in older individuals may mitigate the selection of oncogenic mutations, potentially reducing cancer risk. This insight could inform future therapeutic strategies for cancer prevention and treatment, especially in the elderly population. In summary, our research unveils the role of autophagy in modulating the aging bone marrow microenvironment's impact on CH development. By boosting autophagy in aged mice and observing reduced Tet2 selection, we provide evidence that autophagy plays a crucial role in shaping the oncogenic landscape. This underscores the potential of autophagy-enhancing interventions in countering age-related oncogenic effects. Citation Format: Amy N. Briggs. Exploring how aging-associated changes in autophagy dictate the development of leukemic disease [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B027.