MiR-181a/b and -c/d act as tumor suppressors in MLL-rearranged leukemia by targeting the MLL-complex

Mixed lineage leukemia (MLL) translocations are found in over 70% of infant leukemia. The wildtype MLL gene is involved in chromatin modification by methylating histone H3 (H3K4) and is crucial for leukemogenesis by interacting with the MLL-fusion proteins.

MiR-181 was one of the first miRNAs described in the hematopoietic system and is repressed in MLL-rearranged AML. Here we show that forced expression of miR-181a/b and miR-181c/d bicistrons in MLL-rearranged leukemic cell lines decreased cell viability, cell growth, colony-formation and induced apoptosis. miR-181a/b and -c/d target the 3'UTR of the wildtype MLL gene, measured by microarray analysis, qRT-PCR and luciferase reporter assays. In addition, the AF4 (AFF1) gene, one of the most frequent translocation partner of MLL in pediatric as well in adult ALL, and an essential component of the MLL complex is targeted. Thus miR-181a/b and -c/d act as tumor suppressors in MLL-rearranged leukemias by repressing MLL and AF4, two essential components of the MLL-complex.