Program in Molecular Biology

MLL is a very large, 432 kDa protein with homology to Drosophila trithorax. It is involved in the proper maintenance of expression of downstream target genes including genes of the HOX cluster. HOX genes are involved in body pattern formation as well as in the differentiation pattern of hematopoietic precursor cells. It is unknown how MLL functions, but it is thought to involve a mechanism acting at the level of chromatin. Leukemias with translocations of MLL produce fusion proteins that consist of the amino portion of MLL fused in frame with one of many different partner genes. We are particularly interested in studies regarding the MLL-CBP fusion, which we identified. We have created murine in vitro and in vivo models of MLL-CBP leukemia that recapitulates the human disease. We are also developing inducible tissue culture systems for these fusions. We will use these model systems to determine how MLL chimeric fusion protein functions differ from wild type MLL function. We use a variety of approaches that include protein biochemistry and chromatin remodeling, protein/DNA binding and interaction assays, cDNA microarray analysis, and in vitro hematopoietic differentiation systems.

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