Recently, the fusion gene TEL/AML1 was cloned from children with B-lineage acute lymphoblastic leukemia (ALL). This disease is the most common childhood cancer, and it affects about 4 in 100,000 children in the United States. TEL/AML1 results from a chromosomal translocation between chromosomes 12 and 21, the t(12:21)(pl13;q22). Gene fusion occurs between TEL, located at chromosome 12 band p13, and AML1, located on chromosome 21 band q22. Although the t(12;21) is rarely seen by cytogenetic analysis, the TEL/AML1 fusion is detected in about 25-30% of childhood ALL by using molecular analysis. In addition, almost always the leukemic cells with TEL/AML1 have deletion of the normal TEL allele. Thus, the t(12;21) is unusual in that it requires two different mutations affecting the same gene: the inactivation of one allele of TEL, and the fusion of the second TEL allele to AML1. AML1 is a DNA-binding transactivator involved in several other different translocations associated with myeloid leukemias. TEL is a member of the ETS family of transcription factors and contains a helix-loop-helix (HLH) motif at the N-terminal, necessary for protein dimerization. The working hypothesis is that TEL/AML1 is an altered transcription factor that inappropriately affects genes involved in B cell differentiation. In support of this hypothesis, results show that TEL/AML1 represses the activation by AML1. In addition, the investigators believe that, because the HLH motif is present in the normal TEL and in the TEL/AML1 fusion, the normal TEL might dimerize with TEL/AML1 and inactivate the inappropriate regulation by the chimeric gene. This would explain progressive deletion of the normal TEL allele. The long term objective of the proposal is to dissect the molecular mechanisms by which this chimeric protein affects the development of the hematopoietic cell and leads to leukemia. The major questions addressed in this proposal are: What proteins interact with TEL/AML1? Which genes does it regulate? and How does the leukemia progress? By using a combination of biochemical and molecular cloning techniques and tissue culture studies, the investigator will identify the proteins with which the chimeric genes interact and assess their role in cell transformation. Furthermore, they will use genetically altered animals which express the human fusion protein to evaluate the progress of the disease and to determine how hematopoietic genes are affected by the chimeric proteins. The experiments outlined in this proposal will allow them to begin to dissect the effects of TEL/AML1 in hematopoiesis and its contribution to leukogenesis.
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