Bmi1 overexpression in the cerebellar granule cell lineage of mice affects cell proliferation and survival without initiating medulloblastoma formation.
BMI1 is a potent inducer of neural stem cell self-renewal and neural progenitor cell proliferation during development and in adult tissue homeostasis. It is overexpressed in numerous human cancers - including medulloblastomas, in which its functional role is unclear. We generated transgenic mouse lines with targeted overexpression of Bmi1 in the cerebellar granule cell lineage, a cell type that has been shown to act as a cell of origin for medulloblastomas. Overexpression of Bmi1 in granule cell progenitors (GCPs) led to a decrease in cerebellar size due to decreased GCP proliferation and repression of the expression of cyclin genes, whereas Bmi1 overexpression in postmitotic granule cells improved cell survival in response to stress by altering the expression of genes in the mitochondrial cell death pathway and of Myc and Lef-1. Although no medulloblastomas developed in ageing cohorts of transgenic mice, crosses with Trp53(-/-) mice resulted in a low incidence of medulloblastoma formation. Furthermore, analysis of a large collection of primary human medulloblastomas revealed that tumours with a BMI1(high) TP53(low) molecular profile are significantly enriched in Group 4 human medulloblastomas. Our data suggest that different levels and timing of Bmi1 overexpression yield distinct cellular outcomes within the same cellular lineage. Importantly, Bmi1 overexpression at the GCP stage does not induce tumour formation, suggesting that BMI1 overexpression in GCP-derived human medulloblastomas probably occurs during later stages of oncogenesis and might serve to enhance tumour cell survival.
Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK.
Hourinaz
H
Behesti
Heeta
H
Bhagat
Adrian M
AM
Dubuc
Michael D
MD
Taylor
Silvia
S
Marino
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002453:Cell Cycle; D019070:Cell Lineage; D049109:Cell Proliferation; D002470:Cell Survival; D002528:Cerebellar Neoplasms / Q000209:etiology / Q000235:genetics / Q000473:pathology; D002531:Cerebellum / Q000166:cytology* / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D016158:Genes, p53; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000209:etiology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008959:Models, Neurological; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D000072079:Patched Receptors; D063150:Polycomb Repressive Complex 1 / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics; D059467:Transcriptome; D015854:Up-Regulation
D051792:Basic Helix-Loop-Helix Proteins; D000072079:Patched Receptors; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; C500943:Atoh1 protein, mouse; C069077:BMI1 protein, human; C489421:Bmi1 protein, mouse