It is now well established that the molecular consequences of the t(14;18) translocation is the deregulation of the bcl-2 proto-oncogene. Our work has shown that bcl-2 gene deregulation acts to extend the viability of follicular center B lymphocytes by overriding the normal endogenous apoptotic, or programmed cell death, mechanisms. The affected cells are then susceptible to acquiring complementing genetic lesions which result in malignant transformation and tumor progression. It has subsequently been shown that bcl-2 is expressed in a variety of hematopoietic neoplasms independent of the presence of the t(l4;18). These findings imply that examining apoptotic regulatory mechanisms is of primary importance to the issue of lymphomagenesis. Our proposal outlines a systematic approach to: 1) Quantitate susceptibility of malignant lymphoma cells to chemotherapeutic induced apoptosis as a means to establish apoptosis sensitivity as a prognostic indicator of therapeutic response. 2) Quantitate the expression of bcl-2 protein, using computerized Image analysis and molecular techniques, in order to directly assess the relevance of bcl-2 gene expression to the susceptibility of individual tumors to undergo drug-induced apoptosis and patient response to therapy. 3) Assess the extent and functional significance of molecular lesions of pE3 and Fas/APO-1, two genes known to be associated with the, induction of apoptosis, in low grade and transformed lymphomas and develop the clinical correlations of these findings. Our preliminary data suggests that disruption of normal apoptotic cell death mechanisms is the primary pathogenic event in these low growth fraction tumors. It is our intention to provide the scientific framework for establishing a rational approach to evaluate chemotherapeutic agents based on their ability to induce apoptosis.
| Mirkovic, N; Voehringer, D W; Story, M D et al. (1997) Resistance to radiation-induced apoptosis in Bcl-2-expressing cells is reversed by depleting cellular thiols. Oncogene 15:1461-70 |
| Fernandez, A; Fosdick, L J; Marin, M C et al. (1995) Differential regulation of endogenous endonuclease activation in isolated murine fibroblast nuclei by ras and bcl-2. Oncogene 10:769-74 |
