Myeloid translocation genes differentially regulate colorectal cancer programs

Abstract

Myeloid translocation genes (MTGs), originally identified as chromosomal translocations in acute myelogenous leukemia, are transcriptional corepressors that regulate hematopoietic stem cell programs. Analysis of The Cancer Genome Atlas (TCGA) database revealed that MTGs were mutated in epithelial malignancy and suggested that loss of function might promote tumorigenesis. Genetic deletion of MTGR1 and MTG16 in the mouse has revealed unexpected and unique roles within the intestinal epithelium. Mtgr1−/− mice have progressive depletion of all intestinal secretory cells, and Mtg16−/− mice have a decrease in goblet cells. Furthermore, both Mtgr1−/− and Mtg16−/− mice have increased intestinal epithelial cell proliferation. We thus hypothesized that loss of MTGR1 or MTG16 would modify Apc1638/+-dependent intestinal tumorigenesis. Mtgr1−/− mice, but not Mtg16−/− mice, had a 10-fold increase in tumor multiplicity. This was associated with more advanced dysplasia, including progression to invasive adenocarcinoma, and augmented intratumoral proliferation. Analysis of ChIP-seq datasets for MTGR1 and MTG16 targets indicated that MTGR1 can regulate Wnt and Notch signaling. In support of this, immunohistochemistry and gene expression analysis revealed that both Wnt and Notch signaling pathways were hyperactive in Mtgr1−/− tumors. Furthermore, in human colorectal cancer (CRC) samples MTGR1 was downregulated at both the transcript and protein level. Overall our data indicates that MTGR1 has a context dependent effect on intestinal tumorigenesis.

MTG16 is a tumor suppressor in colitis-associated carcinoma

“…Furthermore, a number of nonsynonymous mutations have been identified in MTG16 in sporadic CRC samples, all of which suggests that MTG16 would function as a tumor suppressor in sporadic colon cancer as it does in inflammatory tumorigenesis (17). However, we have recently demonstrated in the WNT-dependent Apc 1638/+ murine polyp model that loss of MTG16 did not affect adenoma initiation (11). We believe that these results reflect important differences in the molecular mechanisms of CAC and sporadic CRC.…”

“…Recent work has implicated the myeloid translocation genes (MTGs) in intestinal inflammation, stem cell function, and epithelial repair -all processes contributing to the development of CAC (9)(10)(11)(12)(13). The MTG family includes MTG16 (CBFA2T3), MTGR1 (CBFA2T2), and MTG8 (RUNX1T1) (14).…”

Mtg16-dependent repression of E protein activity is required for early lymphopoiesis

“…has reported SNVs across all three MTG family members in multiple tumor types. The lack of an apparent mutational hotspot suggests that MTG family members may function as tumor suppressors, and this hypothesis is borne out in mouse models in which the loss of either Mtgr1 or Mtg16 triggered intestinal tumor formation in both APC min -driven and inflammatory-induced tumor models (Barrett et al, 2011;McDonough et al, 2017;Parang et al, 2016;Parang et al, 2015;Poindexter et al, 2015;Williams et al, 2013).…”

Combined Analysis of the Aberrant Epigenetic Alteration of Colorectal Cancer

“…Actually, previous studies indicated that HSPA1A [18,19], UNC5C [20,21], CBFA2T3 [22,23], NPTX2 [24,25], EPHX4 [26], and AQP1 [27][28][29] have been reported to be associated with CRC. This result also suggested the feasibility of our present results.…”