title: MTGR1 is required for tumorigenesis in the murine AOM/DSS colitis-associated carcinoma model.
abstract: Myeloid Translocation Gene, Related-1 (MTGR1) CBFA2T2 is a member of the Myeloid Translocation Gene (MTG) family of transcriptional corepressors. The remaining two family members, MTG8 (RUNX1T1) and MTG16 (CBFA2T3) are identified as targets of chromosomal translocations in acute myeloid leukemia (AML). Mtgr1(-/-) mice have defects in intestinal lineage allocation and wound healing. Moreover, these mice show signs of impaired intestinal stem cell function. Based on these phenotypes, we hypothesized that MTGR1 may influence tumorigenesis arising in an inflammatory background. We report that Mtgr1(-/-) mice were protected from tumorigenesis when injected with azoxymethane (AOM) and then subjected to repeated cycles of dextran sodium sulfate (DSS). Tumor cell proliferation was comparable, but Mtgr1(-/-) tumors had significantly higher apoptosis rates. These phenotypes were dependent on epithelial injury, the resultant inflammation, or a combination of both as there was no difference in aberrant crypt foci (ACF) or tumor burden when animals were treated with AOM as the sole agent. Gene expression analysis indicated that Mtgr1(-/-) tumors had significant upregulation of inflammatory networks, and immunohistochemistry (IHC) for immune cell subsets revealed a marked multilineage increase in infiltrates, consisting predominately of CD3(+) and natural killer T (NKT) cells as well as macrophages. Transplantation of wild type (WT) bone marrow into Mtgr1(-/-) mice, and the reciprocal transplant, did not alter the phenotype, ruling out an MTGR1 hematopoietic cell-autonomous mechanism. Our findings indicate that MTGR1 is required for efficient inflammatory carcinogenesis in this model, and implicate its dysfunction in colitis-associated carcinoma. This represents the first report functionally linking MTGR1 to intestinal tumorigenesis.
authors.affiliation: Department of Medicine/Gastroenterology, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Caitlyn W
authors.initials: CW
authors.lastname: Barrett
authors.forename: Barbara
authors.initials: B
authors.lastname: Fingleton
authors.forename: Amanda
authors.initials: A
authors.lastname: Williams
authors.forename: Wei
authors.initials: W
authors.lastname: Ning
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Fischer
authors.forename: Mary K
authors.initials: MK
authors.lastname: Washington
authors.forename: Rupesh
authors.initials: R
authors.lastname: Chaturvedi
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
authors.forename: Scott W
authors.initials: SW
authors.lastname: Hiebert
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Williams
mesh_terms: D000818:Animals; D001397:Azoxymethane; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C110408:CBFA2T2 myeloid-transforming gene-related protein; D012097:Repressor Proteins; D016264:Dextran Sulfate; D001397:Azoxymethane