CCSG Pilot: The Hidden Cost of Drinking: How Alcohol Abuse Ages Hematopoietic Stem Cells & Paves the Way For Cancer

ABSTRACT Chronic alcohol consumption (CAC) has been directly linked to multiple types of cancer1. Of importance to this application, CAC is associated with pancytopenia, diminished immune responses, increased childhood leukemia rates in children exposed in utero, and increased risk of developing clonal hematopoiesis of indeterminate potential (CHIP)2-6. CHIP arises from clonal competition between hematopoietic stem cells (HSCs) and results in the increased production of defective -often hyperinflammatory- innate immune cells and reduced production of lymphoid cells. The altered function of mature CHIP immune cells increases the risk for many diseases, including cardiovascular disease (CVD), chronic liver and lung diseases, and cancer7-8. Aging accelerates the development and progression of CHIP9. Given that CAC causes DNA damage and disrupts the DNA repair and DNA damage response (DDR) in HSCs, we hypothesize that CAC accelerates HSC aging, exacerbates CHIP development, and reduces immune functions like immune surveillance and tumor immunity10-12. The primary goals of this pilot proposal are to untangle the complex effects of CAC on the hematopoietic system and to understand the implications for cancer of solid tissues. To achieve these goals, we will: (1) investigate the effects of CAC on HSC aging, and (2) elucidate the molecular pathways linking CAC to CHIP and immune dysfunction. Capitalizing on the unique response of the hematopoietic system to CAC may allow for the development of novel therapies to prevent the morbidity and mortality associated with CAC.