This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The focus of this research proposal is continued study of the MLL gene, which undergoes frequent rearrangement with various chromosomal regions, resulting in leukemogenic MLL fusion genes. One long term objective is to understand the mechanism of chromosome breakage and rearrangement of MLL and its translocation partner genes. The experimental approaches used to study this mechanism are based on the hypothesis that specific proteins act aberrantly within the MLL gene facilitating union of non-homologous genomic regions. One such protein, DNA topoisomerase II has been strongly linked to MLL breaks, but has not been shown to bind directly in the MLL breakpoint region. The experiments described include two assays to show direct binding of proteins (DNA topoisomerase II or as yet unidentified proteins within the MLL breakpoint region. A second goal of the proposed research is to study the role of the MLL fusion genes/proteins in leukemogenesis. We will take a novel approach of using RNA interference to specifically down regulate MLL fusion genes in leukemia cell lines. The goals of these experiments are to 1: test a new and possibly long term method for down regulation of oncogenes in cancer cells and 2: to analyze the down stream effects of fusion gene regulation on cell growth and gene expression. The research proposed within is directly related to human health issues. Identification of molecular interactions of genomic regions of MLL and DNA binding proteins will be important in understanding the mechanism of leukemogenic chromosome rearrangements involving MLL. The RNA interference studies serve to give a better understanding of the molecular genetic pathway of leukemogenesis, and more importantly have potential as a oncogene specific therapeutic approach.
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