A translocation involving chromosomes 14 and 19 has been identified as a recurring abnormality in the malignant cells of patients with chronic lymphocytic leukemia (CLL). The chromosome breakpoint junctions in two such cases have been cloned, and a gene on chromosome 19 has been identified close to these breakpoints. The overall goal of this project is to analyze the relation of this gene to leukemogenesis. Such analysis involves (1) the complete cloning and sequencing of the gene and comparison to previously analyzed genes, and determination of (2) the normal function of the gene, (3) the effect of the t(14;19) on the function of the gene, and (4) the manner in which altered function of the gene may contribute to the development or clinical progression of the leukemia. Evidence concerning the normal function of the gene will be obtained by comparing the sequence of the gene to that of other cloned genes, by determining the intracellular location of the protein product, by biochemical studies, and by studying the expression of the gene in B-lymphocytes and other cell types under various physiological conditions. Analysis of other genes close to the breakpoint of recurring chromosome rearrangements suggests that the function of these genes is modified by the rearrangement and that this functional modification plays a role in the development of the corresponding neoplasms. To determine whether the function of the gene has been altered by the translocation, the sequence of the gene affected by the t(14;19) will be compared with the normal gene, and the expression of the gene in malignant cells with the t(14;19) will be compared to that of CLL cells without the translocation. In order to reproduce the postulated effect of the translocation on the affected cell, appropriate genetic constructs will be transfected into lymphoid cells. The information obtained from these studies will be relevant to the understanding of the normal physiology of lymphocytes and the genetic basis of lymphoid neoplasia.
