The cancer COMPASS: navigating the functions of MLL complexes in cancer

The mixed-lineage leukemia family of histone methyltransferases (MLL1-4, or KMT2A-D) were previously linked to cancer through the founding member, MLL1/KMT2A, which is often involved in translocation-associated gene fusion events in childhood leukemias. However, in recent years, a multitude of tumor exome sequencing studies have revealed that orthologues MLL3/KMT2C and MLL2/KMT2D are mutated in a significant percentage of a large variety of malignancies, particularly solid tumors. These unexpected findings necessitate a deeper inspection into the activities and functional differences between the MLL/KMT2 family members. This review provides an overview of this protein family and its relation to cancers, focusing on the recent links between MLL3/KMT2C and MLL2/4/KMT2D and their potential roles as tumor suppressors in an assortment of cell types.