The ALL-1 gene located at 11q23 is rearranged in a series of reciprocal translocations with at least a dozen specific regions on a variety of chromosomes. These chromosome abnormalities are associated with acute lymphocytic leukemia and acute myeloid leukemia. Recently, we cloned the breakpoint cluster region from chromosome 11, as well as the gene spanning it, which we termed ALL-1. ALL-1 is the human homologue of Drosphilia trithorax, a gene with a critical role in regulating the Antennapedia and Bithorax homeotic gene families. In addition, we have shown that the consequence of 11q23 abnormalities is the fusion of ALL-1 to genes from the partner chromosomes and this results in production by chimeric RNAs and proteins. Three of the partner genes have now been cloned by us and others were found to share sequence homologies and/or common motifs. Here we propose to extend these findings and to clone five additional genes fused to ALL-1 in leukemias with 11q23 abnormalities, in order to determine their relationship to one another and to other genes, and to develop diagnostic tools. We propose to generate transgenic mice expressing some of the chimeric proteins to test whether the latter induce leukemia and determine which one of the reciprocal products is the oncogene. We will try to demonstrate transforming activity of the oncogene in cultured cells in order to complement the results obtained from transgenic mice, as well as to facilitate assays that could be used to examine the biological activity of in vitro-generated mutants. These studies should delineate the elements within ALL-1 and the partner proteins which play a direct role in induction of leukemia. To further investigate the mechanism by which the oncogene induces leukemia, we will generate antibodies specific to the normal and oncogenic ALL-1 proteins and use them to look for differences between the normal and oncogenic ALL-1 proteins with regard to intracellular localization, abundance, and possible aggregation with specific proteins into an active complex. In parallel, we will examine whether the presence of the oncogenic protein in cells with 11q23 abnormalities affects the abundance or the properties of the normal protein.
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