Bmi1 is required for tumorigenesis in a mouse model of intestinal cancer

Abstract

The epigenetic regulator BMI1 is upregulated progressively in a wide variety of human tumors including colorectal cancer. In this study, we assessed the requirement for Bmi1 in intestinal tumorigenesis using an autochthonous mouse model in which Apc was conditionally ablated in the intestinal epithelium. Germline mutation of Bmi1 significantly reduced both the number and size of small intestinal adenomas arising in this model, and it acted in a dose-dependent manner. Moreover, in contrast to wildtype controls, Bmi1−/− mice showed no increase in median tumor size, and a dramatic decrease in tumor number, between 3 and 4 months of age. Thus, Bmi1 is required for both progression and maintenance of small intestinal adenomas. Importantly, Bmi1 deficiency did not disrupt oncogenic events arising from Apc inactivation. Instead, the Arf tumor suppressor, a known target of Bmi1 epigenetic silencing, was upregulated in Bmi1 mutant tumors. This was accompanied by significant upregulation of p53, which was confirmed by sequencing to be wildtype, and also elevated apoptosis within the smallest Bmi1−/− adenomas. By crossing Arf into this cancer model, we showed that Arf is required for the induction of both p53 and apoptosis, and it is a key determinant of the ability of Bmi1 deficiency to suppress intestinal tumorigenesis. Finally, a conditional Bmi1 mutant strain was generated and used to determine the consequences of deleting Bmi1 specifically within the intestinal epithelium. Strikingly, intestinal-specific Bmi1 deletion suppressed small intestinal adenomas in a manner that was indistinguishable from germline Bmi1 deletion. Thus, we conclude that Bmi1 deficiency impairs the progression and maintenance of small intestinal tumors in a cell autonomous and highly Arf-dependent manner.

BMI1 induces an invasive signature in melanoma that promotes metastasis and chemoresistance

“…These treated animals (here called Braf/Pten) develop metastatic melanomas (Dankort et al 2009;Damsky et al 2011). We crossed a Bmi1 conditional allele (Maynard et al 2014 into this Braf/Pten model and confirmed that topical 4-OHT application yielded efficient recombination of the Bmi1 allele in the skin (Supplemental Fig. S6A).…”

“…BRaf CA ;Pten ex5lox and Tyr::CreER mice (Jackson) were crossed to BMI1 fl/fl mice (Maynard et al 2014). Localized tumors were induced with 1 µL of 8.3mg/mL 4-OHT (70% Z-isomer; Sigma) in ethanol vehicle.…”

“…BMI1 was originally identified as an oncogene, and subsequent studies showed that BMI1 maintains the self-renewal and proliferative capacity of adult stem cells via transcriptional silencing of the p16-INK4a, p19-ARF, and p21-Cip1 tumor suppressor loci (Park et al 2004;Valk-Lingbeek et al 2004). Accordingly, BMI1 loss was found to impair the development of various autochthonous tumor types at least in part via derepression of p16-INK4a, p19-ARF, and p21-Cip1 (Lessard and Sauvageau 2003;Dovey et al 2008;Maynard et al 2014). Notably, several of these studies reported impaired proliferative and self-renewal potential of the tumor-initiating cells (Lessard and Sauvageau 2003;Dovey et al 2008;Maynard et al 2014), establishing that BMI1 plays a key role in both adult stem cells and tumor-initiating cells.…”

“…Accordingly, BMI1 loss was found to impair the development of various autochthonous tumor types at least in part via derepression of p16-INK4a, p19-ARF, and p21-Cip1 (Lessard and Sauvageau 2003;Dovey et al 2008;Maynard et al 2014). Notably, several of these studies reported impaired proliferative and self-renewal potential of the tumor-initiating cells (Lessard and Sauvageau 2003;Dovey et al 2008;Maynard et al 2014), establishing that BMI1 plays a key role in both adult stem cells and tumor-initiating cells. However, this does not rule out other mechanisms of BMI1's oncogenic action, particularly with regard to tumor progression.…”

The intestinal epithelial cell cycle

“…Mutation of the polycomb complex oncogene B lymphoma Mo-MLV insertion region 1 homologue (Bmi1) dose-dependently reduced both the number and the size of small intestinal adenomas in a conditional APC knockout model. The Arf tumour suppressor, a target of Bmi1 epigenetic silencing, was upregulated in such tumours and is required for the induction of both p53 and apoptosis observed because of Bmi1 deficiency [51].…”