Somatic noncoding mutations create de novo transcription factor binding sites near the TAL1, LMO1, and LMO2 transcription oncogenes in T-ALL. (A) Insertions in the upstream noncoding elements of TAL1 create a de novo MYB binding site that leads to recruitment of coactivators and the formation of an H3K27ac-positive super-enhancer that drives oncogenic TAL1 expression. (B) Similarly, indels create de novo MYB binding sites at either (1) an upstream distal enhancer leading to distal promoter activation or (2) an intermediate promoter in intron 1, which both can drive LMO2 oncogene activation. (C) A single nucleotide mutation creates a de novo MYB binding motif in a distal enhancer element of the LMO1 proto-oncogene. CBP, CREB-binding protein. Professional illustration by Patrick Lane, ScEYEnce Studios.