MLL repression domain interacts with histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor C-terminal-binding protein

The MLL (mixed-lineage leukemia) gene is involved in many chromosomal translocations associated with acute myeloid and lymphoid leukemia. We previously identified a transcriptional repression domain in MILL, which contains a region with homology to DNA methyltransferase. In chromosomal translocations, the MILL repression domain is retained in the leukemogenic fusion protein and is required for transforming activity of MLL fusion proteins. We explored the mechanism of action of the MILL repression domain. Histone deacetylase 1 interacts with the MILL repression domain, partially mediating its activity; binding of Cyp33 to the adjacent MLL-PHD domain potentiates this binding. Because the MILL repression domain activity was only partially relieved with the histone deacetylase inhibitor trichostatin A, we explored other protein interactions with this domain. Polycomb group proteins HPC2 and BMI-1 and the corepressor C-terminal-binding protein also bind the MILL repression domain. Expression of exogenous BMI-1 potentiates MILL repression domain activity. Functional antagonism between MII and Bmi-1 has been shown genetically in murine knockout models for 11411 and Bmi-1. Our new data suggest a model whereby recruitment of BMI-1 to the MILL protein may be able to modulate its function. Furthermore, repression mediated by histone deacetylases and that mediated by polycomb group proteins may act either independently or together for MILL function in vivo.