The molecular functions of common and atypical MLL fusion protein complexes

Mixed-lineage leukemia (MLL) fuses with a variety of partners to produce a functionally altered MLL complex that is not expressed in normal cells, which transforms normal hematopoietic progenitors into leukemia cells. Because more than 80 fusion partners have been identified to date, the molecular functions of MLL fusion protein complexes appear diverse. However, over the past decade, the common functions utilized for leukemic transformation have begun to be elucidated. It appears that most (if not all) MLL fusion protein complexes utilize the AF4/ENL/P-TEFb and DOT1L complexes to some extent. Based on an understanding of the underlying molecular mechanisms, several molecular targeting drugs are being developed, opening paths to novel therapies. Here, we review the recent progress made in identifying the molecular functions of various MLL fusions and categorize the numerous fusion partners into several functionally-distinct groups to help discern commonalities and differences among various MLL fusion protein complexes. •Functional commonalities and disparities of various MLL fusion protein complexes are categorically described.•MLL fusion protein complexes target transcriptionally-active CpG-rich promoters.•MLL fusion protein complexes commonly recruit the AF4 family/ENL family/P-TEFb complex to activate transcription.•Complex components of MLL fusion proteins are exploited as targets for molecular therapy.