Hematopoietic-specific heterozygous loss of DNMT3A exacerbates colitis-associated colon cancer Journal Article
| Authors: | Feng, Y.; Yuan, Q.; Newsome, R. C.; Robinson, T.; Bowman, R. L.; Zuniga, A. N.; Hall, K. N.; Bernsten, C. M.; Shabashvili, D. E.; Krajcik, K. I.; Gunaratne, C.; Zaroogian, Z. J.; Venugopal, K.; Casellas Roman, H. L.; Levine, R. L.; Chatila, W. K.; Yaeger, R.; Riva, A.; Jobin, C.; Kopinke, D.; Avram, D.; Guryanova, O. A. |
| Article Title: | Hematopoietic-specific heterozygous loss of DNMT3A exacerbates colitis-associated colon cancer |
| 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. © 2023 Feng et al. |
| Keywords: | genetics; mutation; mouse; animal; animals; mice; colonic neoplasms; carcinogenesis; colon tumor; heterozygosity loss; loss of heterozygosity; colitis-associated cancer; colitis-associated neoplasms; dnmt3a protein, mouse |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 220 |
| Issue: | 11 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2023-11-06 |
| Start Page: | e20230011 |
| Language: | English |
| DOI: | 10.1084/jem.20230011 |
| PUBMED: | 37615936 |
| PROVIDER: | scopus |
| PMCID: | PMC10450614 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work