The BCL-2 gene was initially discovered because of its involvement in t(14;18) translocations that occur in the majority of follicular non- Hodgkin's lymphomas (NHLs), a common low-grade form of lymphoma which is nevertheless presently incurable. Since then, rearrangements of the BCL-2 gene dur to a t(14;18) or other chromosomal translocations have been detected in about 30% of aggressive NHLs. The protein encoded by BCL-2 is unique among oncogenes in that it resides in mitochondria and causes cell accumulation by decreasing the rate of cell death, rather than by increasing the rate of cell proliferation. Recent data indicate that BCL-2 overexpression blocks """"""""programmed cell death"""""""" (also termed, """"""""apoptosis""""""""), a mechanism of cellular demise that is induced by many chemotherapeutic drugs. Consequently, hematolymphoid cells containing activated BCL-2 genes are resistant to killing by many anti-cancer drugs and x-irradiation. Given that BCL-2 can increase cellular resistance to chemotherapeutic drugs, it seems likely that patients whose NHLs have deregulated BCL-2 expression may experience a worse clinical outcome than those with histologically similar tumors lacking activation of this oncogene. To test this hypothesis, we will evaluate BCL-2 gene structure and expression in biopsy specimens from patients enrolled in therapeutic trials sponsored by the Eastern Cooperative Oncology Group (ECOG). By evaluating the status of the BCL-2 gene in the setting of well-controlled clinical trials, we will be able to statistically assess the prognostic significance of BCL-2 for particular groups of NHL patients. PCR technology will also be applied to bone marrow and blood samples for detecting small numbers of t(14;18)- containing tumors cells; this information will be compared with routine histopathological methods for detection of disease and the data correlated with clinical outcome. Taken together, these molecular investigations of the BCL-2 gene in patients with NHLs will permit clinico-pathological correlations that may ultimately contribute to improved strategies for patient treatment.
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