Leukemogenic MLL-ENL fusions induce alternative chromatin states to drive a functionally dichotomous group of target genes. MLL-ENL fusion proteins

MLL fusions are leukemogenic transcription factors that enhance transcriptional elongation through modification of chromatin and RNAPolII. Global transcription rates and chromatin changes accompanying the transformation process were monitored by nascent-RNA-seq and ChIP-seq identifying 165 targets separated into two distinct clades. ME5 genes bound MLL-ENL at the promoter, relied on Dot1l mediated histone methylation and coded preferentially for transcription factors including many homeobox genes. A distinct ME3 group accumulated MLL-ENL beyond the termination site, was dependent on P-TEFb mediated phosphorylation of RNAPolII for transcription and translated mainly into proteins involved in RNA biology and ribosome assembly. This dichotomy was reflected by a differential sensitivity towards small molecule inhibitors suggesting the necessity of a combinatorial strategy for therapeutic treatment of MLL-induced leukemia.