Abstract 7358: Cigarette smoking is associated with worse prognosis in myelodysplastic syndromes and causes inflammation and hematopoietic alterations in murine models

Abstract Introduction: Cigarette Smoking has been associated strongly with solid tumors but the causative links with myeloid malignancies have not been well elucidated. Also, the effects of smoking on hematopoiesis have not been explored in vivo. Results: A highly diverse cohort of Myelodysplastic syndrome (MDS) patients (N=128) including 37% Hispanic and 29% African American subjects was studied. Overall survival was found to be significantly reduced in subjects with previous smoking histories (N=78) when compared to never smokers (N= 58), (P value = 0.04; Median Survival 2130 days vs 4620 days). This was not due to significant differences in age, sex, IPSS, blast counts, mutations between the groups. Next, to determine the effects of smoking in vivo, we optimized a cigarette smoke machine that allowed us to expose mice (C57B/6) to 6 cigarettes a day, 3 times a week for one month. Mice exposed to cigarette smoking exhibited signs of reduced activity and showed raised levels of inflammatory mediators, Interleukin-1β (IL1β) and histamine, while the anti-inflammatory protein Interleukin -10 decreased when compared to controls. Mice exposed to cigarette smoking showed reduced white cell counts. Increased hemoglobin was also seen reflecting exposure to smoke. To assess for qualitative stem cell alterations we performed competitive transplantation experiments using CD45.2 donors exposed to smoking using CD45.1 recipients. Smoking exposure led to reduced donor chimerism at 4 months after transplants, when compared to controls. This difference was reduced at 8 and 12 months, demonstrating that smoking exposure led to reduced progenitor functionality, reflected in early chimerism defects. Cigarette smoke condensate (CSC) collected from the smoke machine’s artificial lung was chemically analyzed and showed high levels of nicotine and known carcinogens Acetaldehyde, Formaldehyde, Benzo(a)pyrene, Toluene, Benzene, and Nitrosamines (NNN, NAT, NAB, NNK). We administered CSC via intratracheal injections chronically for 4 months (3 times a week) to an independent cohort of mice. Mice again demonstrated an increase in inflammatory IL-1β and histamine and murine bronchial macrophages treated with CSC exhibited to an inflammatory transcriptomic signature and proteomic validation of increased IL-1β. Lastly, treatment of primary human CD34+ stem and progenitors with CSC resulted in a decreased production of hematopoietic cell colonies, validating the in vivo findings of bone marrow suppression. Conclusion: We demonstrate that history of cigarette smoking is associated worse overall survival in MDS. We also demonstrate that exposure to cigarette smoking leads to inflammation and hematopoietic alterations in vivo, potentially accounting for adverse clinical outcomes in hematologic malignancies. Citation Format: Tanya Verma, Divij Verma, Srabani Sahu, Kith Pradhan, Ritesh Aggarwal, Sakshi Jasra, Seyedeh Shareh Dehghani, Hui Zhang, Mason Spodek, Ioannis Mantzaris, Marina Konopleva, Mendel Goldfinger, Amit Verma, Dean Hosgood, Aditi Shastri, Yiyu Zou. Cigarette smoking is associated with worse prognosis in myelodysplastic syndromes and causes inflammation and hematopoietic alterations in murine models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7358.