Background: The SET domain is a conserved C-terminal domain that characterizes proteins of the MLL family, including MLL3. The MLL SET domain is a histone H3 Lys4 (K4)-specific methyltransferase whose activity is stimulated with acetylated H3 peptides. MLL3 maps to 7q36, a chromosome region frequently deleted in myeloid leukaemia. The deduced MLL3 4,911-amino acid protein is more closely related to MLL2 than to MLL1 or MLL4. MLL3 has 6 plant homeodomain (PHD) fingers preceded by a cys-rich ZNF1 domain in its N terminus, a high mobility group (HMG) box, an ATPase alpha-beta signature, and a leucine zipper motif in its central region, and 2 C-terminal FY (phe-tyr) motifs and the SET domain preceded by a ZNF2 domain in its C terminus. The predicted protein also contains several putative nuclear localization motifs. Isoform II lacks ZNF1 and the PHD.