TAL1 activation in T-Cell acute lymphoblastic leukemia: A novel oncogenic 3' neoenhancer.

T-cell acute lymphocytic leukemia protein 1 (TAL1) is one of the most frequently deregulated oncogenes in T-cell acute lymphoblastic leukemia (T-ALL). Its deregulation can occur through diverse in cis-alterations, including SIL-TAL1 microdeletions, translocations with Tcell Receptor (TCR) loci and, more recently described upstream intergenic non-coding mutations. These mutations consist of recurrent focal microinsertions that create an oncogenic neo-enhancer accompanied with activating epigenetic marks. This observation laid the groundwork for an innovative paradigm, the activation of proto-oncogenes via genomic alterations of non-coding intergenic regions. However, for the majority of TAL1 expressing (TAL1+) T-ALLs, the deregulation mechanism remains "unresolved". We took advantage of H3K27ac and H3K4me3 ChIP-seq data of eight T-ALLs, including five TAL1+ cases and identified a putative novel oncogenic neo-enhancer downstream of TAL1 in an "unresolved" monoallelic TAL1+ case. A rare but recurrent somatic heterozygous microinsertion within this region creates a de novo binding site for MYB transcription factor (TF). Here, we demonstrate that this mutation leads to increased enhancer activity, gain of active epigenetic marks and TAL1 activation via recruitment of MYB. These results highlight the diversity of non-coding mutations that can drive oncogene activation.