The ALL-1 gene located at human chromosome 11q23 is frequently rearranged in acute leukemias. The rearrangements are usually caused by chromosome translocations resulting in production of chimeric proteins composed of a segment of ALL-1 linked to a partner protein. In addition, a second type of ALL-1 linked to a partner protein. In addition, a second type of ALL-1 rearrangement was discovered in which N-terminal portion of the protein is tandemly repeated. ALL-1 is the human homologue of Drosophila trithorax (TRX) which plays an important roles in maintaining expression of homeotic genes during development. TRX is a member of the TRX-G family of genes. The products of some of these genes have been now shown to be components of multimeric protein complexes whose role is to open chromatin. Our recent studies indicate that ALL-1 too is present within a multi-meric protein complex. In the first part of the application, we propose to purify to homogeneity the multi-protein large complex containing normal ALL-1, and to subsequently determine whether the leukemogenic ALL-1 chimeric derivatives are also present within such a complex or within an altered version of it. In the second project, we propose to further study a novel gene, recently cloned by us, which is likely to correspond to the human homologue of Drosophila ash1. We will focus on generation of mice null for this gene, on characterization of the protein product and on attempts to determine whether the gene is involved in human cancer. In the final part of the application, on characterization of the protein product and on attempts to determine whether the gene is involved in human cancer. In the final part of the application, we propose to generate chimeric mice harboring the partially tandem duplicated ALL-1 and to determine whether mice develop leukemia.
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