The goal of this program is to improve the understanding, treatment and survival of patients with malignant lymphoma. The focus of all of the projects is on the diffuse aggressive lymphoma (DAL). An interactive and interdisciplinary effort has been organized around three specific areas which take advantage of significant new findings and developments by the program investigators and by others in the field. I. Clinical Trial This is a clinical trial exploring a regimen of increased treatment dose intensity for the patients who can now be identified at the time of diagnosis to have a poor prognosis with conventional treatments. Built into this trial is an investigation, using molecular probes, as to the existence of tumor cells in the peripheral blood of the patients, and the development of technology for the introduction of drug resistance genes into the hematopoietic stem cells. II. Tumor Cell Biology New receptors and intracellular signaling pathways of cell death have been defined in DAL cells and these receptors are being targeted with antibodies and with synthetic peptide ligands. The control of transcription of the c- myc oncogene is being studied and compared in normal and in DAL cells. III. Pathogenesis of DAL DAL cells have been discovered to have a strong preference for the use of an antigen binding receptor encoded by the VH4.21 immunoglobulin gene. The protein products of this gene have been discovered to have a cytotoxic effect on normal B cells. These two observations lead to a number of hypotheses which are being tested about the role of the antigen binding receptors in the pathogenesis of DAL. In addition, novel oncogenes have been discovered at the sites of chromosomal rearrangements in lymphoid tumor cells. The mechanism of action of these oncogenes in lymphogenesis is being explored.