We propose to investigate the molecular basis of the 11q23 chromosome rearrangements involved in the pathogenesis and progression of human leukemias. Most of the program focuses on the role of the ALL-1 gene and of its fusion with many other genes in the pathogenesis and progression of human acute leukemias including secondary leukemias. The ALL-1 gene has regions of homology with the Drosophila trithorax (trx) gene, that is the positive regulator of homeobox genes within the bithorax and antennapedia complexes. Thus the ALL-1 gene may play and important role in mammalian development. We propose to characterize the ALL-1 transcripts and genomic organization to clone and characterize many genes that fuse with ALL-1 to give origin to transforming oncogenes, to determine the developmental pattern of expression of mRNA and proteins of the ALL-1 gene, to isolate and characterize the genes such as AF-4 and AF-9 that fuse with ALL-1, to investigate their expression during development, to define the genetic elements for ALL-1 expression, and to assess the role of the chimeric genes in leukemogenesis in transgenic mice. We are also planning to investigate the function of the trx proteins in Drosophila, and to identify the trx response elements and the proteins that interact with the trx products. Finally, we intend to investigate the elk-1 gene that may be important not only in tumorigenesis but also in cell growth and differentiation. Very interestingly the elk-1 protein is homologous to the c-fos regulatory factor p62 TCF. This program consists of four closely interrelated and interacting projects and of an administrative core component. The common goal of the program is to achieve a better understanding of the genes and of the molecular mechanisms involved in the pathogenesis and progression of human leukemias.
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