The 8;21 translocation, t(8;21) (q22.1;q22.3), is a frequent nonrandom chromosome rearrangement seen almost exclusively in the M2 subtype of acute myelogenous leukemia (AML). We have isolated the 21q+ chromosome as the only identifiable human material in a somatic cell hybrid, and have demonstrated that the c-mos oncogene, which has been localized to the region of the chromosome 8 breakpoint, is neither rearranged nor translocated to chromosome 21. We have also identified chromosome 21 specific DNA sequences which are reciprocally translocated to the 8q- chromosome. We now wish to determine if our findings can be generalized to other patients with AML and the 8;21 translocation and to isolate and examine those DNA sequences or genes located at or adjacent to the breakpoints. We will utilize two approaches to identify the breakpoints: 1) screening a complete human cosmid library with DNA probes from the regions where the breaks occur, and 2) a low repeat DNA sequence analysis of the 21q+ chromosome. The actual junction fragment will be isolated from an EMBL-4 Lambda library of the 21q+ chromosome. To examine more directly the c-mos oncogene and those chromosome 21 genes which are translocated to the 8q- chromosome and which may be important to the pathogenesis of this disease, we are actively constructing additional hybrids to isolate both the 8q- and 21q+ chromosomes from several patients with t(8;21) AML. Once those genes which are located at or adjacent to the breakpoints are identified, we will examine the level of transcription of those genes in both somatic cell hybrids and t(8;21)AML cells using a Northern blot analysis. In conjunction with studies designed to detect alterations in gene expression resulting from the 8;21 translocation, we will determine the level of c-myc transcription in the hybrid containing the translocated c-myc gene present in the 21q+ chromosome. These studies will provide information on gene expression in somatic cell hybrids constructed between myeloid leukemic cells and CHO mutants. Information gained from these studies may lead to a better understanding of the etiology of certain types of AML and may help to develop more specific and less toxic forms of therapy.
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