Abstract B93: Investigating the role of the hematopoietic-specific DNMT3A mutations in the aggressive phenotype of colon cancer

Abstract

Abstract Clonal hematopoiesis (CH) is a nonmalignant condition characterized by clonal expansion of one or few hematopoietic stem cells. CH is associated with advanced age and presence of presumed leukemic driver mutations, such as in the DNMT3A gene. Clinical studies show that presence of CH mutations in the bone marrow in patients with solid tumors is associated with unfavorable prognosis and shorter survival. Moreover, CH mutations are enriched in tumor-infiltrating leukocytes compared to peripheral blood. While these observations have profound clinical implications, the understanding of the relationship between mutations in the blood system and aggressive phenotype of solid tumors is still lacking. We hypothesized that bone marrow-derived cells harboring alterations in DNMT3A contribute to tumor-promoting microenvironment through immune imbalance. To this end, we established a mouse model of CH driven by Dnmt3a alterations and are investigating its effect on a well-established colitis-associated colon cancer model (CAC) as a prototypical solid tumor. Wild-type recipient mice were transplanted with bone marrow from animals with: a) heterozygous loss of Dnmt3a (Dnmt3a+/−); b) Dnmt3a R878H point-mutation (Dnmt3aRH); c) wild-type controls (Dnmt3a+/+). Since inflammation is known to promote tumorigenesis, we are testing the sensitivity of engrafted mice to experimental colitis induced by 2.5% dextran sulfate sodium salt (DSS) in drinking water. Animals of all 3 experimental groups will be co-housed to control for cage-to-cage variability in microbiota. We will use total body weight loss, histopathology of harvested colons (swiss roll method)/colitis scores, colon size, and appearance of intestinal contents as a readout for colitis severity. Next, we will investigate AOM/DSS-induced tumorigenesis in CH model, including tumor burden and extent of inflammation between experimental groups. Finally, we will characterize tumor-infiltrating leukocytes that contribute to aggressive CAC phenotype to identify immune populations that engender this tumor-modulating function, including epigenetic and gene expression profiles. Our goal is to understand the relationship between mutations in the blood system and aggressive phenotype of nonhematologic cancers and to nominate potential targets for therapeutic intervention. Citation Format: Yang Feng, Daniil E. Shabashvili, Luisa M. Posada, Kathryn I. Krajcik, Chamara Gunaratne, Olga A. Guryanova. Investigating the role of the hematopoietic-specific DNMT3A mutations in the aggressive phenotype of colon cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B93.