Suppression of Signal Transducer and Activator of Transcription 3–Dependent B Lymphocyte Terminal Differentiation by Bcl-6

Lymphocytes usually differentiate into effector cells within days after antigen exposure, except in germinal centers where terminal differentiation is delayed while somatic hypermutation creates high-affinity antibody mutants. Here we investigate whether arrest of terminal differentiation can be mediated by BCL-6, a transcriptional repressor that is expressed by germinal center B cells and is required for this phase of B cell development. We find that BCL-6 suppresses the differentiation of transformed and primary B cells to plasma cells by inhibiting the signal transducer and activator of transcription 3–dependent expression of the major regulator of plasma cell development, the B lymphocyte–induced maturation protein (Blimp-1). This function of BCL-6 as a repressor of B lymphocyte differentiation may also underlie the association between chromosomal translocations of its gene and B cell lymphomas

The BTB/POZ domain targets the LAZ3/BCL6 oncoprotein to nuclear dots and mediates homomerisation in vivo

The LAZ3/BCL6 gene was identified by its disruption in 3q27 translocations associated with diffuse large cell lymphomas. It is predicted to be a transcription factor as it contains six Krüppel-like Zinc finger motifs and a N-terminal BTB/POZ domain, a protein/protein interaction interface that is widely conserved in Metazoans. Using two antisera raised against non overlapping regions of the predicted ORF, we demonstrate that the LAZ3/BCL6 protein appears as a close ca. 79 kDa doublet in B lymphoid cell lines with either a rearranged or a non rearranged LAZ3/BCL6 locus. By immunofluorescence experiments on transiently transfected COS-1 or NIH3T3 cells, we show that the LAZ3/BCL6 protein displays a punctuated nuclear localisation. This appears to rely on LAZ3/BCL6 proper folding and/or activities as it is impaired in a hormone reversible-fashion through fusion of LAZ3/BCL6 to the ligand-binding domain of the oestrogen receptor. Moreover, deletion of its BTB/POZ domain leads to the disappearance of the nuclear dots although the protein remains nuclear. In addition, by using the yeast two-hybrid system, we show that the LAZ3/BCL6 BTB/POZ domain homomerises in vivo. Thus, the LAZ3/BCL6 BTB/POZ domain has the capability to self-interact and target the protein to discrete nuclear substructures

LAZ3 rearrangements in non-Hodgkin's lymphoma: correlation with histology, immunophenotype, karyotype, and clinical outcome in 217 patients.

We have recently shown that an evolutionary conserved gene LAZ3, encoding a zinc finger protein, is disrupted and overexpressed in some B-cell lymphomas (mainly with a large cell component) that show chromosomal rearrangements involving 3q27. Because the breakpoints involved in these rearrangements are focused in a narrow major translocation cluster (MTC) on chromosome 3, we used genomic probes from this region to study the molecular rearrangements of LAZ3 in a large series of patients (217) with non-Hodgkin's lymphoma (NHL). Southern blot analysis showed LAZ3 rearrangement in 43 patients (19.8%). Rearrangement was found in 11 of the 84 patients (13%) with follicular lymphoma but was most frequent in aggressive lymphoma (diffuse mixed, diffuse large cell, and large cell immunoblastic subtypes), in which 31 of the 114 patients (27%) were affected. The highest proportion of LAZ3 alteration was observed in B-cell aggressive lymphoma (26 of 71 cases, 37%). Eleven of the 32 patients with 3q27 chromosomal abnormality had no LAZ3 rearrangement, suggesting the possibility of LAZ3 involvement outside the MTC. On the other hand, 18 of the 39 patients with LAZ3 rearrangement and available cytogenetic results did not have visible chromosomal break at 3q27, suggesting that almost a half of the rearrangements are not detectable by cytogenetic methods. No statistical association could be found between LAZ3 status and initial features of the disease or clinical outcome in either follicular or aggressive lymphomas. We conclude that LAZ3 alteration is a relatively frequent event in B-cell lymphoma, especially in those of aggressive histology. It could be used as a genomic marker of the disease, and further studies are needed to clarify clinical implications of these alterations