Bmi1 Is Required for Hedgehog Pathway-Driven Medulloblastoma Expansion

Abstract

Inappropriate Hedgehog (Hh) signaling underlies development of a subset of medulloblastomas, and tumors with elevated HH signaling activity express the stem cell self-renewal gene BMI1. To test whether Bmi1 is required for Hh-driven medulloblastoma development, we varied Bmi1 gene dosage in transgenic mice expressing an oncogenic Hh effector, SmoA1, driven by a glial fibrillary acidic protein (GFAP) promoter. Whereas 100% of SmoA1; Bmi1(+/+) or SmoA1;Bmi1(+/-) mice examined between postnatal (P) days 14 and 26 had typical medulloblastomas (N = 29), tumors were not detected in any of the SmoA1;Bmi1(-/-) animals examined (N = 6). Instead, small ectopic collections of cells were present in the region of greatest tumor load in SmoA1 animals, suggesting that medulloblastomas were initiated but failed to undergo expansion into frank tumors. Cells within these Bmi1(-/-) lesions expressed SmoA1 but were largely nonproliferative, in contrast to cells in Bmi1(+/+) tumors (6.2% vs 81.9% PCNA-positive, respectively). Ectopic cells were negative for the progenitor marker nestin, strongly GFAP-positive, and highly apoptotic, relative to Bmi1(+/+) tumor cells (29.6% vs 6.3% TUNEL-positive). The alterations in proliferation and apoptosis in SmoA1;Bmi1(-/-) ectopic cells are associated with reduced levels of Cyclin D1 and elevated expression of cyclin-dependent kinase inhibitor p19(Arf), two inversely regulated downstream targets of Bmi1. These data provide the first demonstration that Bmi1 is required for spontaneous de novo development of a solid tumor arising in the brain, suggest a crucial role for Bmi1-dependent, nestin-expressing progenitor cells in medulloblastoma expansion, and implicate Bmi1 as a key factor required for Hh pathway-driven tumorigenesis.

Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations

“…Nevertheless, the pattern of lineage markers, robust proliferation, and occasional areas of central necrosis seen in GLI2ΔN-expressing tumors described in this report are in keeping with the diagnosis of nodular, BCC-like tumors. Interestingly, the weak transforming potential of activated Smo alleles may be limited to skin, since Smo is a potent oncogene in cerebellum, where it gives rise to medulloblastomas with high penetrance when targeted to neuronal progenitors (50,61,62).…”

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

“…Medulloblastoma, a primitive neuroectodermal tumor, is thought to arise from immature neural progenitors in the cerebellum (Lee et al, 2005). Genomic alterations in components of the Hh signaling pathway have been identified in up to 25% of human medulloblastomas (Michael et al, 2008), consisting of inactivating mutations of Ptch1 and Sufu and/or activating mutations of Smo (Taylor et al, 2002;Hallahan et al, 2004;Oliver et al, 2005;Mao et al, 2006;Thomas et al, 2009;Huse and Holland, 2010). More recently, dysregulated Hh signaling has been shown to be sufficient to generate tumors in either neural stem cell (NSC) or precursor cell populations, implicating a more primitive cell of origin (Schuller et al, 2008;Yang et al, 2008).…”

“…This gene is implicated in the pathogenesis of brain tumors such as glioma (Bruggeman et al, 2007) and medulloblastoma (Leung et al, 2004;Wiederschain et al, 2007;Michael et al, 2008), and is an important epigenetic regulator of fate determination and proliferation in stem cell populations (Valk-Lingbeek et al, 2004;Bracken et al, 2006). Previous reports have suggested that there is a potential link between Hh signaling and Bmi1, alluding to a novel regulatory mechanism whereby an external signaling morphogen interacts with cell-intrinsic epigenetic pathways controlling cell fate programs (Valk-Lingbeek et al, 2004).…”

Calculating a cure for cancer: managing medulloblastoma MATH1-ematically

“…Overexpression of BMI1 is observed in 30-40% of MBs, resulting in inhibition of apoptotic pathways through sups, resulting in inhibition of apoptotic pathways through suppression of p16ink4a and p19arf [31]. Similar to what is described by Flora et al for Math1 [17], deletion of Bmi1 in a medulloblastoma mouse model driven by activated Smo (SmoA1) completely abrogates tumorigenesis [31].…”