The Polycomb transcription repressor BMI1 is highly expressed in human neuroblastomas and is required for the clonogenic self-renewal and tumorigenicity of human neuroblastoma cell lines. The molecular basis of BMI1 action in neuroblastoma cells is not well understood. Here we report that BMI1 has a critical role in stabilizing cyclin E1 by repressing the expression of FBXW7, a substrate-recognition subunit of the SCF E3 ubiquitin ligase that targets cyclin E1 for degradation. BMI1 binds to the FBXW7 locus in vivo and represses its mRNA expression. Overexpression of cyclin E1 or abrogation of FBXW7 induction rescues the cell-death phenotype of BMI1 knockdown. Moreover, MYCN, an oncoprotein in the pathogenesis of high-risk neuroblastomas, is able to counteract the death-inducing effect of BMI1 knockdown by activating CCNE1 transcription. We further show that high cyclin E1 expression is associated with Stage 4 neuroblastomas and poor prognosis in patients. These findings suggest a molecular mechanism for the oncogenic activity of BMI1 and MYCN in neuroblastoma pathogenesis and progression by maintaining cyclin E1 levels. © 2012 Macmillan Publishers Limited All rights reserved.