Follicular lymphoma is one of the few slowly progressing malignancies where disease evolution can be followed through repeated biopsies. In a study of 156 patients, we have observed that the majority of patients with follicular lymphoma and some with diffuse large cell lymphoma have a characteristic t(14;18)(q32.3;q21.3) chromosome translocation with a bcl- 2/IgH gene rearrangement. In addition, 1 to 8 of the 20 additional recurrent chromosome defects were noticed during disease evolution. Some, such as duplication 2p and 3p, correlated with cell phenotype or aggressiveness. In a few cases we and others have found a combined t(14;18) and either t(8;14) or t(8;17) with bcl-2 and c-myc rearrangements. More prevalent chromosomal sites involved in rearrangement include 1p36, 2p13, 3q27, 6q21 and 17q21. The oncogenes fgr, lck, re1, fim-3, myb, ros, fyn and bcl-3, have been mapped to these regions. We plan to use Southern and Northern blot analysis, pulsed field gel electrophoresis and molecular cloning, to determine whether some of these genes are altered during the course of the disease. To this effect, we have prepared genomic libraries from lymphoma samples containing either t(3;14)(q27;q32.3) or t(14;17)(q32.1;q21) to identify the genes affected by these rearrangements. Southern blot analysis of a patient with 2p13 rearrangements suggest that the c-rel oncogene, which has not previously been implicated in human neoplasia, may be the primary gene affected in this region. We have found suggestive evidence of c-rel rearrangement or amplification in seven patients with follicular lymphoma and in one cell line derived from a diffuse large cell lymphoma with inv ins(2;2)(p13;p15p11.2). All patients had very aggressive disease. In the lymphoma cell line, Southern and Northern blot analysis, as well as genomic and cDNA cloning, show that the c-rel oncogene has been truncated at the C-terminus and a hybrid c-rel message produced. DNA sequencing of the breakpoint and the fusion message, followed by expression assays, are planned. Our long range goal is to extend these types of studies to other recurrent breakpoints in order to molecularly characterize the sequential alterations leading to tumor progression, using follicular lymphoma as a model.