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Self-renewing hematopoietic stem cells (HSCs) produce billions of blood cells a day to maintain peripheral blood and immune cells in circulation. Inflammation can alter the balance of steady-state hematopoiesis, and disrupted hematopoiesis can lead to blood disorders or cancers. Over a lifetime of cell divisions, HSCs may acquire somatic mutations that provide a competitive advantage over their wild-type counterparts. The clonal expansion of a mutant HSC population is termed “clonal hematopoiesis” (CH). CH is linked to an increased overall risk of mortality due to incidences of cardiovascular disease and transformation into hematological malignancy. Tobacco and nicotine use remain the leading preventable drivers of cancer risk, and both direct and secondhand exposure to combustible cigarettes or electronic nicotine devices perturbs immune function and hematopoiesis. The World Health Organization estimates more than 100 million people across the world are using electronic cigarettes, or e-cigarettes, but the health impacts of these “safer” e-cigarette alternative have yet to be fully elucidated. E-cigarettes have been associated with inflammation and oxidative stress, which can provide selective pressures for the outgrowth of CHIP mutant cells.Here, we evaluate the impact of e-cigarette vapor and combustible cigarette smoke on in vitro cell inflammatory responses and in vivo long-term hematopoietic differentiation. The overarching goal of this project was to understand further how an inflammatory lifestyle stressor, such as smoking, contributes to aberrant hematopoiesis in wild-type normal stem cells, Tet2- deficient cells, and JAK2V617F mutant cells. In cell-based studies, cigarette smoke extract (CSE) and e-cigarette vapor extract (EVE) consistently suppress LPS-induced TNF-α secretion across macrophage/monocyte models, including primary mouse and human cells and complementary cell lines, indicating a reproducible immunosuppressive effect on mature myeloid cells. To assess consequences of smoking behavior in vivo, we used a custom nose-cone inhalation system to deliver controlled exposures to combustible cigarette smoke or e-cigarette aerosol to mice. Chronic exposure increased myeloid proliferation, a hallmark of HSC aging. Taken together, these results support a model in which tobacco exposures blunt innate immune responsiveness while simultaneously driving myeloid expansion conditions that accelerate hematopoietic aging and promote the expansion of mutant hematopoietic cells.