Disease relevance of Bcl6

• The Bcl6 gene has been identified from the chromosomal translocation breakpoint in B cell lymphomas, and its products are expressed highly in germinal center (GC) B cells [1].
• RESULTS: Massive myocarditis with eosinophilic infiltration occurred in Bcl6-/- mice after 4-6 weeks of age [2].
• Simian AIDS-related lymphoma growth in severe combined immunodeficiency mice is independent of karyotypic abnormalities or Bcl-6 mutations [3].
• Simian AIDS-related lymphomas (sARL) of cynomolgus monkeys infected with a simian immunodeficiency virus (SIVsm) were studied in relation to growth in severe combined immunodeficient (SCID) mice, karyotype abnormalities, and DNA sequence of the first noncoding region of the Bcl-6 gene [3].

High impact information on Bcl6

• We show here that Bcl6-deficient B cells, which cannot develop germinal centers, differentiated into IgM and IgG1 memory B cells in the spleen but barely differentiated into long-lived IgG1 antibody-forming cells in the bone marrow [4].
• Memory B cells without somatic hypermutation are generated from Bcl6-deficient B cells [4].
• Therefore, Bcl6 and germinal center formation are essential for somatic hypermutation, and generation of memory B cells can occur independently of germinal center formation, somatic hypermutation, and Ig class switching [4].
• The magnitude of the increase correlated with Bcl-6 expression in the T cells [5].
• Bcl-6 controlled the generation and maintenance of antigen-specific memory phenotype CD8+ T cells in the spleens of immunized mice [5].

Biological context of Bcl6

• Reconstitution of BCL6 expression in Bcl6(-/-) macrophages results in complete reversion of the morphological phenotype and a significant increase in cell surface CSF1R expression whereas overexpression of the CSF1R corrects the polarization and adhesion structure defects [6].
• The expression of GANP was strikingly correlated with GC formation because Bcl6-deficient mice did not show the up-regulation of GANP [7].
• Expression of BAZF mRNA, like that of Bcl6 mRNA, was induced in activated lymphocytes as an immediate-early gene [8].
• Testicular germ cell apoptosis in Bcl6-deficient mice [9].
• Thus, the IL5BS may act as a silencer element for Bcl6 to repress expression of the IL-5 gene [10].

Anatomical context of Bcl6

• Therefore, Bcl6 is essential for the differentiation of GC B cells [1].
• Disruption of the Bcl6 gene results in an impaired germinal center formation [1].
• To investigate the function of Bcl6 in lymphocytes, we have generated RAG1-deficient mice reconstituted with bone marrow cells from Bcl6-deficient mice (Bcl6(-/-)RM) [1].
• Although there is mounting evidence for the importance and necessity of Blimp-1 in plasma cell development, there is uncertainty as to the role it plays in B cell differentiation of B cell subsets and the way in which it may interact with other transcription factors such as Pax5 and Bcl6 during ASC differentiation [11].
• Thus, Bcl6 may play a role as a stabilizer in protecting spermatocytes from apoptosis induced by stressors [9].

Other interactions of Bcl6

• We showed here that Id2 and Bcl6, both of which inhibit IgE GLT and CSR, are not involved in this inhibitory pathway [12].
• We have identified two intronic regions of mouse prdm1, the gene encoding B lymphocyte-induced maturation protein-1 (Blimp-1), which confer transcriptional repression in response to Bcl-6 [13].
• We also summarize our recent studies on the regulation of Blimp-1, showing direct repression by Bcl-6 and providing evidence for activation by NF-kappaB following toll-like receptor signaling [14].
• Since the activated form of p38 MAP kinase was detected in spermatocytes of adult Bcl6-/- mice, the germ cell apoptosis may be induced by stressors [9].
• Furthermore, overexpression of Bcl6 or Bcl6(POZ-) (Bcl6 deleted with the BTB/POZ domain) induced apoptosis in NIH3T3 cells, and the apoptosis was inhibited by the addition of histone deacetylase inhibitor in the culture [15].

Analytical, diagnostic and therapeutic context of Bcl6

• We found a putative Bcl6-binding sequence (IL5BS) on the 3' untranslated region in the murine and human IL-5 genes, and specific binding of Bcl6 protein to the sequence was confirmed by gel retardation assay and chromatin immunoprecipitation assay [10].
• Binding of Bcl6 in nuclear protein from resting RAW264 cells to murine IL-18BS was detected by gel retardation assay and chromatin immunoprecipitation assay [16].
• The proliferation of Ag-specific memory CD8(+) T cells upon secondary stimulation was dramatically up-regulated in lck-Bcl6 transgenic mice, and the adoptive transfer experiments with Ag-specific naive CD8(+) T cells demonstrated that some of the up-regulation was due to the intrinsic effect of Bcl6 in the T cells [17].
• Sequence analysis of a Bcl-6 gene fragment showed sequence variations indicative of population polymorphism(s) in 10 of 13 sARLs, and no evidence of Bcl-6 mutations [3].

References