Active leukemias are one form of devastating illness in humans. Chromosomal rearrangements identified from these leukemias has led to the identification of the genes responsible for abnormal cellular proliferation. A series of translocation breakpoints and deletions found altered in a subset of human acute leukemias have the similar feature of having one end of the break on human chromosome 11q23. This region has recently been cloned and a large gene (ALL-1) with homology to the Drosophila trithorax gene has been identified. The ALL-1 gene has been found to be fused to a large number of different genes in these human leukemias. This proposal focuses on identifying and manipulating the mouse homolog of the human ALL-1 gene in order to study its role in normal mammalian development. The mouse provides an excellent experimental system for the study of ALL-1 in mammals, since it is possible to directly manipulate the genetic content of the mouse as well as to study all stages of development. In addition, mice that carry altered genes, the result of homologous recombination in embryonic stem cells, are the ultimate model system for determining the normal in vivo role of cellular protooncogenes. This proposal plans to complete the cloning and sequencing of the mouse homolog of the ALL-1 gene and identify and characterize alternatively spliced forms, providing an important basis for understanding the role of ALL-1 in human leukemias. In addition, research will focus on elucidating the pattern of expression of this gene during development with the goal of understanding how this gene is regulated. Finally, we will identify and generate mutant mice lacking All-1 expression to understand its role in development. These mutant mice will provide a foundation for future goals of identifying the functional components of All-1 as well as identifying genes regulated by All-1. It is through an understanding of the mechanisms of action and regulation of the All-1 gene that future research focusing on treatment of these human acute leukemias will be based.
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