ANALYSIS OF LAZ3 (BCL-6) STATUS IN B-CELL NON-HODGKINS-LYMPHOMAS - RESULTS OF REARRANGEMENT AND GENE-EXPRESSION STUDIES AND A MUTATIONAL ANALYSIS OF CODING REGION SEQUENCES

The LAZ3 gene encodes a novel zinc-finger protein that shares homology with several Drosophila transcription factors. This gene was identifi ed by its disruption in translocations involving chromosome 3q27 in di ffuse large-cell lymphomas. To assess the frequency and role of this g ene's involvement in lymphomagenesis and tumor progression, we examine d a series of 170 cases of non-Hodgkin's lymphomas of B-cell lineage f or LAZ3 gene rearrangement, expression, and mutation. The cases includ ed 35 de novo diffuse aggressive lymphomas (DAL; 19 large-cell, 4 mixe d-cell, and 12 large-cell immunoblastic), 52 transformed aggressive ly mphomas derived from follicular lymphomas (TFL), 42 indolent follicula r lymphomas (FL), 14 mantle cell lymphomas (MCL), and 27 small nonclea ved cell lymphomas (SNCL). LAZ3 rearrangements were found in 10 DAL (2 8.6%), 9 TFL (17.3%), and 6 FL (14.3%), but not in any of the SNCL or MCL. LAZ3 rearrangement was not exclusive of bcl-2 rearrangement. Most rearrangement breakpoints mapped to a 10-kb BamHI-Xba I fragment loca ted 5' to the LAZ3 coding sequence, consistent with previously reporte d breakpoint locations. Northern analysis of both rearranged and nonre arranged B-cell lymphoma cases showed similar levels of a transcript o f approximately 3.8 kb, indicating that LAZ3 is broadly expressed in B -cell tumors and is not confined to rearranged cases. To investigate w hether mutation of the LAZ3 gene might contribute to a potential role for this gene in lymphomagenesis, we screened the coding sequences of 13 rearranged cases, 6 nonrearranged cases, and 13 hematopoietic tumor cell lines. Although three probable polymorphisms were identified, mu tations were detected in only 2 rearranged cases. Only 1 of these resu lted in an amino acid substitution. Two cell lines (SU-DHL4 and Molt-4 ) also contained mutations; only one resulted in an amino acid substit ution. We conclude (1) that LAZ3 rearrangements occur in a significant fraction of de novo DAL as well as in a smaller subset of indolent an d transformed follicular lymphomas; (2) that LAZ3 message is expressed in both rearranged and nonrearranged B-cell lymphomas; and (3) that m utation of the LAZ3 gene does not contribute to its putative oncogenic role in most 3q27 translocated B-cell lymphomas. (C) 1995 by The Amer ican Society of Hematology.