Interaction of the MLL-fusion complex with LEDGF/p75. (A) Schematic representation of the MLL-fusion complex. The most common MLL chromosomal translocations result in expression of the N-terminus of MLL and the C-terminus of a fusion partner gene (MLL-fusion). The extreme N-terminus of MLL forms a triple complex with MENIN and LEDGF/p75. The latter recognizes H3K36 di- and trimethylated marks, whereby it tethers the MLL-fusion complex to its targets genes such as HOXA9, MEIS1, and PBX3. (B) Domain structure of wild-type MLL, MLL-fusion, LEDGF/p75, and LEDGF/p52. Wild-type MLL and MLL-fusions contain the MENIN binding domain (MBD) and the LEDGF/p75 binding domain (IBD-interacting motif [IBM]) at its extreme N-terminus. Further downstream, wild-type MLL contains 3 AT-hooks, 2 speckled nuclear localization signals (SNLs), a transcriptional repression domain (TRD), 4 PHD fingers, and a bromodomain. The transactivation domain (TAD) and SET domains are located at the MLL C-terminus. LEDGF/p75 harbors a PWWP (aa 1-93), a nuclear localization signal (NLS), 2 AT hook-like motifs (ATH), 3 charged regions (CRs), and the integrase binding domain (IBD) that binds to MLL. LEDGF/p52 shares similar structural domains but lacks the C-terminal IBD.