Intestinal-specific activatable Myb initiates colon tumorigenesis in mice

Abstract

Transcription factor Myb is overexpressed in most colorectal cancers (CRC). Patients with CRC expressing the highest Myb are more likely to relapse. We previously showed that mono-allelic loss of Myb in an Adenomatous polyposis coli (APC)-driven CRC mouse model (Apc Min/+ ) significantly improves survival. Here we directly investigated the association of Myb with poor prognosis and how Myb co-operates with tumor suppressor genes (TSGs) (Apc) and cell cycle regulator, p27. Here we generated the first intestinalspecific, inducible transgenic model; a MybER transgene encoding a tamoxifen-inducible fusion protein between Myb and the estrogen receptor-α ligand-binding domain driven by the intestinal-specific promoter, Gpa33. This was to mimic human CRC with constitutive Myb activity in a highly tractable mouse model. We confirmed that the transgene was faithfully expressed and inducible in intestinal stem cells (ISCs) before embarking on carcinogenesis studies. Activation of the MybER did not change colon homeostasis unless one p27 allele was lost. We then established that MybER activation during CRC initiation using a pro-carcinogen treatment, azoxymethane (AOM), augmented most measured aspects of ISC gene expression and function and accelerated tumorigenesis in mice. CRC-associated symptoms of patients including intestinal bleeding and anaemia were faithfully mimicked in AOM-treated MybER transgenic mice and implicated hypoxia and vessel leakage identifying an additional pathogenic role for Myb. Collectively, the results suggest that Myb expands the ISC pool within which CRC is initiated while co-operating with TSG loss. Myb further exacerbates CRC pathology partly explaining why high MYB is a predictor of worse patient outcome.Oncogene ( INTRODUCTIONAberrant activation of the WNT pathway (Adenomatous polyposis coli (APC) or β-catenin mutation) is the pre-eminent early event in colorectal cancers (CRC). Nevertheless, parallel activation of other oncogenes including MYB occurs commonly and is reasonably thought to participate in CRC.1 Furthermore, Myb and β-catenin cooperate to regulate the CRC genes MYC and PTGS2 (COX2) 2 along with the intestinal stem cell (ISC) gene, LGR5.3 Elevated MYB transcripts are a common feature of CRC 2,4,5 and high Myb protein is a poor-prognosis indicator. 6 Others have identified MYB and WNT-target gene, AXIN2 as among nine essential and differentially expressed genes in colon cancer. 7 However, although MYB is on occasion amplified in CRC it is rarely (if ever) found to have mutations in coding regions but rather in transcriptional regulatory regions.1 Thus, it remains unclear how MYB specifically participates in colorectal carcinogenesis.The intestine is a rapidly self-renewing tissue maintained by ISCs. The colonic epithelium is composed of the absorptive and the secretory lineages continuously renewed by rapidly cycling intestinal progenitor cells (IPC) generated from ISC.8 ISC are targets for transformation.9 Two kinds of ISCs have been proposed; crypt basal cells (CBC) 10 and ...

Clinical and molecular insights into adenoid cystic carcinoma: Neural crest‐like stemness as a target

“…Myeloblastosis is also required for maintenance of adult stem cells of the colon and brain. In the colon crypts and in colon cancer, it stimulates stem cells required for tissue maintenance and tumor repopulation, respectively . Using a mouse model with inducible tissue specific loss, MYB was also found to be critical for maintenance of neural stem cell progenitors in the adult brain .…”

“…In the colon crypts and in colon cancer, it stimulates stem cells required for tissue maintenance and tumor repopulation, respectively. 111,112 Using a mouse model with inducible tissue specific loss, MYB was also found to be critical for maintenance of neural stem cell progenitors in the adult brain. 113 Interestingly, of MYB's two closely related family members, only MYBL1 expression patterns link it to proliferation of immature neuronal precursor cells.…”

Multigene panel predicting survival of patients with colon cancer

“…Actually, among the 7 genes included, several have been reported to be involved in the pathogenesis of colon cancer. Activation of MYB could induce colon tumorigenesis [35], and it was also selected as a target for antineoplastic therapy [36]. MSLN had been accepted to be a candidate biomarker in colon cancer [37].…”

O-Linked N-Acetylglucosamine (O-GlcNAc) Expression Levels Epigenetically Regulate Colon Cancer Tumorigenesis by Affecting the Cancer Stem Cell Compartment via Modulating Expression of Transcriptional Factor MYBL1

“…Although these members share highly conserved DNA-binding domains and binding site specificities, they appear to have different biological roles (62,63). Studies have shown that Myb proteins play important oncogenic roles in a variety of solid tumors (64), including colon tumor (65)(66)(67)(68). MYBL1 is a strong transcriptional activator (69) and is often co-expressed with other members of the myb family (62), but its function is not as well studied as other members.…”