BMI1 is a target gene of E2F-1 and is strongly expressed in primary neuroblastomas

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Abstract
The oncogene BMI1 encodes a polycomb group transcription factor that is required for embryonic development and self-renewal of stem cells. Despite these important functions little is known about the regulation of BMI1 expression. A cDNA microarray based search for target genes of E2F-1 in neuroblastoma cells expressing a 4-OHT-regulated E2F-1-ER fusion protein identified many hitherto unknown E2F-1 regulated genes. A total of 10% of these genes, including BMI1, encode proteins that function primarily in the regulation of gene expression. The BMI1 promoter contains a putative E2F binding site that was required for the activation of a BMI1 promoter-dependent reporter construct by E2F-1. Chromatin immunoprecipitation revealed 4-OHT-dependent binding of E2F-1-ER and binding of endogenous E2F-1 to the BMI1 promoter in tumor cells. We have previously shown activation of the oncogene MYCN by E2F. Thus, in neuroblastomas deregulated E2F-1 can activate two oncogenes, MYCN and BMI1 that are known to co-operate in tumor formation. Consistent with a role of Bmi1 in neuroblastoma tumorigenesis we found strong Bmi1 expression in primary neuroblastomas. Our results reveal a novel link between E2F and polycomb transcription factors and suggest a role of Bmi1 in neuroblastomas.