Epigenetic changes in pediatric neuroblastoma may contribute to the aggressive 
pathophysiology of this disease, but little is known about the basis for such 
changes. In this study, we examined a role for the DNA methyltransferase DNMT3B, 
in particular, the truncated isoform DNMT3B7, which is generated frequently in 
cancer. To investigate if aberrant DNMT3B transcripts alter DNA methylation, 
gene expression, and phenotypic character in neuroblastoma, we measured DNMT3B 
expression in primary tumors. Higher levels of DNMT3B7 were detected in 
differentiated ganglioneuroblastomas compared to undifferentiated 
neuroblastomas, suggesting that expression of DNMT3B7 may induce a less 
aggressive clinical phenotype. To test this hypothesis, we investigated the 
effects of enforced DNMT3B7 expression in neuroblastoma cells, finding a 
significant inhibition of cell proliferation in vitro and angiogenesis and tumor 
growth in vivo. DNMT3B7-positive cells had higher levels of total genomic 
methylation and a dramatic decrease in expression of the FOS and JUN family 
members that comprise AP1 transcription factors. Consistent with an established 
antagonistic relationship between AP1 expression and retinoic acid receptor 
activity, increased differentiation was seen in the DNMT3B7-expressing 
neuroblastoma cells following treatment with all-trans retinoic acid (ATRA) 
compared to controls. Our results indicate that DNMT3B7 modifies the epigenome 
in neuroblastoma cells to induce changes in gene expression, inhibit tumor 
growth, and increase sensitivity to ATRA.