A translocation involving chromosomes 14 and 19 is a recurring abnormality in the malignant cells of patients with chronic lymphocytic leukemia (CLL) and is also occasionally seen in acute lymphoblastic leukemia and de novo lymphoma. The breakpoints junctions in four cases of the t(14;19) have cloned and sequenced, and a gene, BCL3, has been identified close to these breakpoints. BCL3 is homologous to a number of genes which are involved in control of the cell cycle or in cell lineage determination; it is the first candidate proto-oncogene to be reported in this gene family. Expression of the gene is increased in leukemic cells with the translocation, and expression in normal peripheral blood cells is stimulated by mitogenic agents. The overall goal of this project is to charactedze this new gene in detail, with emphasis on its role in leukemogenesis. Such an analysis involves determining (1) the normal pattern of gene expression and the sequences which regulate its expression, (2) the normal function of the gene product, (3) the manner in which the translocation leads to altered expression, and (4) the manner in which altered expression contributes to the development or clinical progression of leukemia. Evidence concerning the normal function of the gene will be obtained by determining the intracellular localization of the protein product and by a variety of biochemical studies. The underlying hypothesis of this work is that BCL3 overexpression results in phenotypic changes in B-cells which contribute to leukemogenesis. Appropriate genetic constructs which provide highlevel expression of the gene will be transfected into lymphoid cells in order to reproduce this postulated effect. Similar constructs will be microinjected into mouse zygotes to produce transgenic mice, to determine whether such animals develop neoplasms and, if so, whether they resemble human CLL. We will also analyze unselected CLL samples to determine the frequency of the t(14;19) and whether BCL3 may be overexpressed by other mechanisms in some cases of CLL without the translocation. The phenotype of CLL cells is somewhat paradoxical, for they are less responsive to mitogens than normal lymphocytes in vitro; however, this may reflect the behavior of the corresponding normal cell, the CD5+ B-lymphocyte. It is unclear whether abnormalities such as the t(14;19) increase the proliferative rate compared to normal CD5+ B-cells, or, instead, increase the lifespan of the CLL cell. Thus, further analysis of the function of BCL3 may help to clarify the pathogenesis of this common, but poorly understood neoplasm. In addition, determining the molecular pathways in which BCL3 is involved may aid in the discovery of additional genes important in oncogenesis.
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