Proposed model for the oncogenic conversion of MLL fusions. (A) The physiologic situation of MLL functions. Taspase1-cleaved MLL is assembled into the holo-complex and binds to target promoter regions. This occurs via the N-terminally bound MEN1/LEDGF protein complex that allows binding to many transcription factors. The PHD domain is able to read histone core particles, whereas the SET domain allows it to write epigenetic signatures (H3K4_me2/3). Associated CREBP and MOF are able to acetylate nucleosomes. CYP33 allows switching into the repressor mode by enabling the docking of a Polycomb group complex composed of BMI1, HPC2, CtBP, and several HDACs. This enables the removal of acetyl groups from nucleosomes or transcription factors to shut down gene transcription. (B) In the case of a chromosomal translocation, the intrinsic regulatory mechanism of MLL becomes destroyed. The disrupted MLL portions are fused to protein sequences deriving from a large amount of different partner genes (n > 80). The N-terminal portion of MLL retains the ability to bind MEN1 and LEDGF, and thus, to bind to target promoter regions. Depending on the fusion sequence (AF4, AF5, LAF4, AF9, ENL, AF10), MLL-X fusions may recruit the endogenous AF4 complex that contains P-TEFb and the histone methyltransferases DOT1L, NSD1, and CARM1. This activates gene transcription and results in enhanced epigenetic signatures (H3K79_me2/3). The C-terminal portion retains CREBBP and MOF binding capacity, as well as the SET domain. In some cases (AF4, AF5, LAF4), the N-terminal fused protein sequences allow binding to P-TEFb and directly to the largest subunit of RNA polymerase II to enhance the process of transcriptional elongation. In addition, the fused protein sequences still bind NSD1 and DOT1L.