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Hematopoietic-specific heterozygous loss of Dnmt3a exacerbates colitis-associated colon cancer
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10450614/ https://www.ncbi.nlm.nih.gov/pubmed/37615936 http://dx.doi.org/10.1084/jem.20230011 |
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author | Feng, Yang Yuan, Qingchen Newsome, Rachel C. Robinson, Troy Bowman, Robert L. Zuniga, Ashley N. Hall, Kendra N. Bernsten, Cassandra M. Shabashvili, Daniil E. Krajcik, Kathryn I. Gunaratne, Chamara Zaroogian, Zachary J. Venugopal, Kartika Casellas Roman, Heidi L. Levine, Ross L. Chatila, Walid K. Yaeger, Rona Riva, Alberto Jobin, Christian Kopinke, Daniel Avram, Dorina Guryanova, Olga A. |
author_facet | Feng, Yang Yuan, Qingchen Newsome, Rachel C. Robinson, Troy Bowman, Robert L. Zuniga, Ashley N. Hall, Kendra N. Bernsten, Cassandra M. Shabashvili, Daniil E. Krajcik, Kathryn I. Gunaratne, Chamara Zaroogian, Zachary J. Venugopal, Kartika Casellas Roman, Heidi L. Levine, Ross L. Chatila, Walid K. Yaeger, Rona Riva, Alberto Jobin, Christian Kopinke, Daniel Avram, Dorina Guryanova, Olga A. |
author_sort | Feng, Yang |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10450614 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-104506142023-08-26 Hematopoietic-specific heterozygous loss of Dnmt3a exacerbates colitis-associated colon cancer Feng, Yang Yuan, Qingchen Newsome, Rachel C. Robinson, Troy Bowman, Robert L. Zuniga, Ashley N. Hall, Kendra N. Bernsten, Cassandra M. Shabashvili, Daniil E. Krajcik, Kathryn I. Gunaratne, Chamara Zaroogian, Zachary J. Venugopal, Kartika Casellas Roman, Heidi L. Levine, Ross L. Chatila, Walid K. Yaeger, Rona Riva, Alberto Jobin, Christian Kopinke, Daniel Avram, Dorina Guryanova, Olga A. J Exp Med Brief Definitive Report 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. Rockefeller University Press 2023-08-24 /pmc/articles/PMC10450614/ /pubmed/37615936 http://dx.doi.org/10.1084/jem.20230011 Text en © 2023 Feng et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Brief Definitive Report Feng, Yang Yuan, Qingchen Newsome, Rachel C. Robinson, Troy Bowman, Robert L. Zuniga, Ashley N. Hall, Kendra N. Bernsten, Cassandra M. Shabashvili, Daniil E. Krajcik, Kathryn I. Gunaratne, Chamara Zaroogian, Zachary J. Venugopal, Kartika Casellas Roman, Heidi L. Levine, Ross L. Chatila, Walid K. Yaeger, Rona Riva, Alberto Jobin, Christian Kopinke, Daniel Avram, Dorina Guryanova, Olga A. Hematopoietic-specific heterozygous loss of Dnmt3a exacerbates colitis-associated colon cancer |
title | Hematopoietic-specific heterozygous loss of Dnmt3a exacerbates colitis-associated colon cancer |
title_full | Hematopoietic-specific heterozygous loss of Dnmt3a exacerbates colitis-associated colon cancer |
title_fullStr | Hematopoietic-specific heterozygous loss of Dnmt3a exacerbates colitis-associated colon cancer |
title_full_unstemmed | Hematopoietic-specific heterozygous loss of Dnmt3a exacerbates colitis-associated colon cancer |
title_short | Hematopoietic-specific heterozygous loss of Dnmt3a exacerbates colitis-associated colon cancer |
title_sort | hematopoietic-specific heterozygous loss of dnmt3a exacerbates colitis-associated colon cancer |
topic | Brief Definitive Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10450614/ https://www.ncbi.nlm.nih.gov/pubmed/37615936 http://dx.doi.org/10.1084/jem.20230011 |
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