The MLL gene at chromosome band 11q23 is frequently rearranged in de novo acute myeloid and acute lymphoblastic leukemia and laos in therapy- related leukemia in patients who have previously received topoisomerase II inhibitors. The consequence of these translocations is the formation of a chimeric gene topoisomerase II inhibitors. The consequences of these translocations if the formation of a chimeric gene that consists of N-terminal sequences from MLL fused in frame to C-terminal sequences of its partner genes. The (11;19)(q23;p13.1) translocation is one of the most common of 11q23 aberrations. Previously, we have cloned the ELL gene from the 19p13.1 breakpoint and have characterize its tissue distribution, we have cloned the ELL gene from the 19p13.1 breakpoint and have characterized its tissue distribution, subcellular localization, and expression in murine development. Recently, ELL has been found to associate with the basal transcription machinery and to function as an RNA polymerase II elongation associate with the basal transcription machinery and to function as a RNA polymerase II elongation factor. However, its aberrant functions when used to MLL remain unknown. The focus of this proposal is the identification and characterization of proteins that interact with ELL, the development of in vitro assays to undertake structure-function studies of the MLL-ELL fusion protein, and the generation of a mouse model to characterize the consequence of the expression of MLL-ELL fusion genes. Because ELL is one of the few MLL partner genes with a known function, the data generated from these studies should provide insight into the pathobiology of other 11q23 leukemias. The development of these models will provide insight into the pathobiology of other 11q23 leukemias. The development of these models will provide insight into the pathobiology of other 11q23 leukemias. The development of these models will provide critical reagents for the characterizations of 11q23 leukemias, the analysis of the contributions of individual domains within the MLL fusion genes to leukemogenesis, and the development of novel treatment strategies for this common subtype of leukemia.
