Overexpression of the TAL1 oncogene occurs frequently in T cell acute lymphoblastic leukemia (T-ALL), but the mechanism driving overexpression is not known in some cases. Now, A. Thomas Look, Richard Young and colleagues show that somatic mutation of a noncoding element creates a binding site for the MYB transcription factor and drives expression of the TAL1 oncogene (Science doi:10.1126/science.1259037; 13 November 2014). The authors first observed a broad region of aberrant histone H3 lysine 27 acetylation (H3K27ac) encompassing the TAL1 transcriptional start site in Jurkat cells, a T-ALL cell line with unexplained overexpression of TAL1. They identified a 12-bp insertion in the region and further identified indels in the TAL1 enhancer in 8 of 146 T-ALL clinical samples. They determined that all of the indels created MYB binding motifs, driving expression in reporter assays, and showed by chromatin immunoprecipitation that MYB bound to the de novo site in Jurkat cells. The authors also used CRISPR/Cas9 technology to show that disruption of the insertion site in Jurkat cells abolished TAL1 expression and H3K27ac. This work provides an example of the de novo generation of an oncogenic enhancer.