Heterologous Promoters Fused to BCL6 by Chromosomal Translocations Affecting Band 3q27 Cause Its Deregulated Expression During B-Cell Differentiation

Abstract

Abstract The BCL6 gene encodes a POZ/Zinc-finger protein, which acts as a sequence-specific transcriptional repressor. It is expressed in B cells within the germinal centers (GC) and is required for GC formation. In ≈40% of diffuse large cell lymphomas (DLCL) and ≈14% of follicular lymphomas (FL), the BCL6 gene is rearranged by chromosomal translocations, which juxtapose heterologous promoters and 5′ untranslated sequences derived from other chromosomes to the BCL6 coding domain or by mutations in the 5′ regulatory region. To understand the functional consequence of the chromosomal translocations, we have studied the patterns of expression of the promoters found juxtaposed to BCL6 in DLCL and FL during B-lineage differentiation. Distinct heterologous 5′ untranslated regions (IGH, IGL, TTF) were identified fused to the BCL6 coding domain by analysis ofBCL6 cDNAs in two DLCL cases and one mixed follicular lymphoma (MxFL). These three sequences, as well as three other previously identified BCL6 fusion partners (IGHG3, BOB1,H4), were studied for their pattern of expression during B-lineage differentiation by Northern blot analysis of B-cell lines representative 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 expression ranging from constitutive expression throughout B-cell differentiation to persistent expression in immunoblasts and plasma cells. These results indicate that the expression ofBCL6 is deregulated as a consequence of fusion to heterologous promoter regions. The persistent expression of activated BCL6may contribute to lymphomagenesis by blocking B-cell differentiation within the GC.