The mixed lineage leukemia (MLL) gene was identified due to its involvement in chromosomal translocations with a variety of translocation partners resulting in human acute myeloid or acute lymphoid leukemia. Our purification of several of the translocation partners led to the identification of the Super Elongation Complex (SEC), which includes the transcription elongation factors from the ELL family as well as the RNA Polymerase II (Pol II) c-terminal domain kinase P-TEFb. One goal of this proposal is to identify genes that are misregulated as a consequence of the chimeric protein recruiting SEC to MLL target genes, which can result in loss of the transcription elongation checkpoint control and increased expression of genes, contributing to oncogenesis. Identifying such genes could provide new therapeutic targets in the treatment of these leukemias. Another goal is to elucidate the molecular mechanisms for the recruitment of endogenous MLL as part of MLL/COMPASS and the MLL chimera/SEC to their sites on chromatin. We are also investigating the regulation of the stability of endogenous MLL and how this regulation contributes to leukemogenesis. Although MLL is frequently mutated in leukemia, the MLL3 and MLL4 branches of the COMPASS family are frequently mutated in a large number of tumors. Since MLL3 and MLL4 COMPASS regulate histone H3K4 monomethylation at transcriptional enhancers, we hypothesize that the loss of MLL3/4 COMPASS function at enhancers contributes to misexpression of tumor suppressors or oncogenes. Determining how these COMPASS mutations contribute to oncogenesis could lead to new strategies for combating these cancers.
Members of the MLL/COMPASS family of chromatin modifiers are highly mutated in numerous human cancers. For example, in certain types of childhood leukemias, the MLL gene undergoes chromosomal rearrangements resulting in translocations with other genes leading to the expression of chimeric proteins resulting in the misregulation of gene expression that promotes oncogenesis, while MLL3 and MLL4 COMPASS are mutated in a large variety of tumors, possibly related to their role in modifying chromatin at gene regulatory elements. The goal of this R50 proposal is to determine the underlying mechanisms of how the normal and mutant forms within the COMPASS family function in order to devise novel cancer therapeutics.
