Specific rearrangements of chromosome 21 have been characteristically associated with human leukemia. The most common rearrangement is the 8;21 translocation found exclusively in the M2 subtype of acute myelogenous leukemia. Another specific translocation between chromosomes 3 and 21 has been found in the blast crisis of chronic myelogenous leukemia. We have been the first investigators to isolate and characterize the AML 8;21 translocation. We propose to identify a rearrangement in the 8;21 translocation using anonymous DNA probes from the proximal 21q22.3 region and pulsed-field electrophoresis. The molecular cloning of the actual breakpoint will follow using both conventional genomic and specialized chromosome jumping libraries. We will also isolate and characterize the CML 3:21 translocation and determine the relationship of these breakpoints to other chromosome 3 and 21 leukemia related translocations we have already isolated. We will also use an oligonucleotide probe to isolate and regionally localize chromosome 21 recombinant clones from a flow sorted library which contain Not I sites. These probes will be used to access the Lehrach Not I jumping library which significantly facilitate the development of a chromosome 21 physical linkage map. These studies should allow the isolation of genes involved in the pathogenesis of human leukemia and may provide insight into the mechanism of the increased risk of leukemia in patients with Down Syndrome.
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