The focus of this program project is the study of MLL associated leukemogenesis. The long-term goal is to understand 'the process of leukemogenesis associated with MLL-fusion genes resulting from translations involving cliromosome 11 band q23. These leukemias include several subsets: de novo adult and pediatric leukemia, therapy-related leukemia subsequent to treatment of other cancers with topoisomerase-II inhibitors, and infant leukemia that apparently arise in utero. Projects 1 and 2 will address aspects of the initiation and progression of the leukemogenic process: Project 1 will explore the hypothesis that apoptotic nucleases play a significant role in the generation of the chromosome 11 translocations that initiate the leukemic process both in treatment related leukemia and in infant leukemia. It will also search for mutations that allow cells to survive apoptosis after undergoing rearrangements, and will search for MLL rearrangements in human patients subjected to cytotoxic therapy. Project 2 will try to identify secondary mutations that push the initiated clones into clinically detectable leukemia using animal models. The fusion proteins of MLL conserve the N-terminal part of MLL, and replace its C-terminal part with one from the partner proteins. Project 2 will also try to dissect these different domains of MLL to determine which ones are essential for, and which ones are inhibitory of transformation. Project 3 will ask a related question testing the hypothesis that Cyp33, a protein that binds the third PHD finger of MLL, inhibits the transactivating activity of MLL by controlling the function of its repression domain and its effect on target gene chromatin structure. The role of Cyp33 as a sensor for non-coding RNAs generated in the intergenic regions of the MLL, target genes will also be studied in Project 3. Project 4 will test the hypothesis that MLL regulates its target genes through modifications in the histones and chromatin structure of their promoters and enhancers. It also will look at the possibility mat modifications (i.e.: acetylation) of the MLL protein itself modulate its function as a transactivator of the target genes. A Retroviral Core will provide help to these projects. These studies will provide a better understanding of the leukemogenic process and its relationship to hematopoiesis regulation by epigenetic processes and its disruption by genetic mutation. The results of these studies may allow the design of new prevention and therapeutic strategies.
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