HETEROLOGOUS PROMOTERS FUSED TO BCL6 BY CHROMOSOMAL TRANSLOCATIONS AFFECTING BAND 3Q27 CAUSE ITS DEREGULATED EXPRESSION DURING B-CELL DIFFERENTIATION

The BCL6 gene encodes a POZ/Zinc-finger protein, which acts as a seque nce-specific transcriptional repressor. It is expressed in B cells wit hin the germinal centers (GC) and is required for GC formation. In app roximate to 40% of diffuse large cell lymphomas (DLCL) and approximate to 14% of follicular lymphomas (FL), the BCL6 gene is rearranged by c hromosomal translocations, which juxtapose heterologous promoters and 5' untranslated sequences derived from other chromosomes to the BCL6 c oding domain or by mutations in the 5' regulatory region. To understan d the functional consequence of the chromosomal translocations, we hav e studied the patterns of expression of the promoters found juxtaposed to BCL6 in DLCL and FL during B-lineage differentiation. Distinct het erologous 5' untranslated regions (IGH, IGL, TTF were identified fused to the BCL6 coding domain by analysis of BCL6 cDNAs in two DLCL cases and one mixed follicular lymphoma (MxFL). These three sequences, as w ell as three other previously identified BCL6 fusion partners (IGHG3 B OB1, H4), were studied for their pattern of expression during B-lineag e differentiation by Northern blot analysis of B-cell lines representa tive of the pre-B, B, immunoblast, and plasma cell stages. In contrast to BCL6, whose transcription is activated only in B cells within the GC, all of the other sequences displayed a broader pattern of expressi on ranging from constitutive expression throughout B-cell differentiat ion to persistent expression in immunoblasts and plasma cells. These r esults indicate that the expression of BCL6 is deregulated as a conseq uence of fusion to heterologous promoter regions. The persistent expre ssion of activated BCL6 may contribute to lymphomagenesis by blocking B-cell differentiation within the GC. (C) 1998 by The American Society of Hematology.