B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. As predicated by its prenatal origin, infant B-ALL (iB-ALL) shows an exceptionally silent DNA mutational landscape, suggesting that alternative epigenetic mechanisms may significantly contribute to its leukemogenesis. We have extensively characterized the DNA methylome and the transcriptome lansdcape of 40 patients with de novo MLL rearranged (MLLr) and non-MLLr iB-ALL leukemias uniformly treated according to Interfant-99/06 protocol. iB-ALL methylome signatures display a plethora of common and specific alterations associated with chromatin states related to enhancer and transcriptional control. Further methylome-transcriptome integration identified consistent cancer-cell vulnerabilities, revealed a robust iB-ALL-specific gene expression-correlating dmCpG signature and confirmed an epigenetic control of AP-1 and RUNX members in reshaping the molecular network of MLLr iB-ALL. Pharmacological inhibition or functional ablation of AP-1 activity resulted in dramatic in vitro and in vivo leukemia proliferation defects, providing rationale for new potential therapeutic avenues in iB-ALL. This dataset contains information related to dataframes, databases, scripts and supplementary material mentioned in the original manuscript.