Hematopoietic-specific heterozygous loss of <i>Dnmt3a</i> exacerbates colitis-associated colon cancer
Yang Feng, Qingchen Yuan, Rachel C. Newsome, Troy M. Robinson, Robert L. Bowman, Ashley N. Zuniga, Kendra N. Hall, Cassandra M. Bernsten, Daniil E. Shabashvili, Kathryn I. Krajcik, Chamara Gunaratne, Zachary Zaroogian, Kartika Venugopal, Heidi L. Casellas Román, Ross L. Levine, Walid K. Chatila, Rona Yaeger, Alberto Riva, Christian Jobin, Daniel Kopinke, Dorina Avram, Olga A. Guryanova
Abstract
Clonal hematopoiesis (CH) is defined as clonal expansion of mutant hematopoietic stem cells absent diagnosis of a hematologic malignancy. Presence of CH in solid tumor patients, including colon cancer, correlates with shorter survival. We hypothesized that bone marrow-derived cells with heterozygous loss-of-function mutations of DNMT3A, the most common genetic alteration in CH, contribute to the pathogenesis of colon cancer. In a mouse model that combines colitis-associated colon cancer (CAC) with experimental CH driven by Dnmt3a+/Δ, we found higher tumor penetrance and increased tumor burden compared with controls. Histopathological analysis revealed accentuated colonic epithelium injury, dysplasia, and adenocarcinoma formation. Transcriptome profiling of colon tumors identified enrichment of gene signatures associated with carcinogenesis, including angiogenesis. Treatment with the angiogenesis inhibitor axitinib eliminated the colon tumor-promoting effect of experimental CH driven by Dnmt3a haploinsufficiency and rebalanced hematopoiesis. This study provides conceptually novel insights into non-tumor-cell-autonomous effects of hematopoietic alterations on colon carcinogenesis and identifies potential therapeutic strategies.