Many B-cell leukemias and lymphomas have characteristic chromosomal abnormalities. The t(14;18) translocation is found in follicular lymphoma, the t(11;14) translocation in diffuse small and large cell lymphoma, and the t(8;14), t(2;8) or t(8;22) translocation is seen in Burkitt's lymphoma or other high grade lymphoproliferative malignancies. It was previously shown that rearrangements of the bcl-2 gene are associated with the t(14;18) translocation, rearrangements of the bcl-1 gene with t(11;14) translocation, and rearrangements of the c-myc oncogene with Burkitt's lymphoma. I intend to study the evolution of B-cell malignancies. I hypothesize that rearrangements of the bcl-2 gene lead to the occurrence of additional chromosomal abnormalities. I plan to use cDNA to screen patient samples for translocation involving the bcl-2, bcl-1, or c-myc gene as well as additional alterations of these genes. I will rescreen specimens from patients during the course of their disease. Cell lines from patient samples will be developed. Genomic libraries will be prepared in order to clone the involved loci. The cloned rearrangements will be characterized by restriction enzyme mapping, analysis of the nucleotide sequence, and I will study their transcripts. I further want to investigate whether the infection of hematopoietic cells with the bcl-2 and the c-myc oncogenes in retrovirus vectors results in malignant transformation. In addition, I want to establish whether infection of B-cells, T-cells and other hematopoietic cells with retroviruses containing the bcl-2 and the c-myc oncogenes results in the establishment of continuous cell lines. These experiments should provide important insights into the mechanisms involved in the control of B- and T-cell proliferation.
|Gauwerky, C E; Huebner, K; Isobe, M et al. (1989) Activation of MYC in a masked t(8;17) translocation results in an aggressive B-cell leukemia. Proc Natl Acad Sci U S A 86:8867-71|
|Gauwerky, C E; Haluska, F G; Tsujimoto, Y et al. (1988) Evolution of B-cell malignancy: pre-B-cell leukemia resulting from MYC activation in a B-cell neoplasm with a rearranged BCL2 gene. Proc Natl Acad Sci U S A 85:8548-52|