Cooperative transcriptional repression by BCL6 and BACH2 in germinal center B-cell differentiation

Abstract

Key Points BCL6 and BACH2 cooperatively regulate GC B-cell development. The cooperative action of BCL6 and BACH2 is through both transcriptional and biochemical mechanisms.

Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP

“…However, the survival of MYC-rearranged Myc high Bcl-2 high GCB double-positive lymphoma patients remains significantly worse than other double-positive lymphoma patients (Figures 6g and h). The biological investigation (in this regard, ≥ 70% is a better cutoff compared with ≥ 40% for Myc high in our cohort) revealed that MYC activation was associated with significantly increased or decreased expression of genes and proteins involved in cell proliferation (e.g., pAKT, Ki-67), apoptosis (p53, Bcl-2, FAS, BCL2A1, PEG10, HINT1, TRAF1), differentiation (PRDM1, BLIMP-1, BACH2 (which represses PRDM1) 43 ), noncoding RNAs (eg, LINC00152, GAS5, SNHG1, NAPSB) and microRNAs, microenvironment, and immune responses, as well as cellof-origin markers ( Figure 3 and Tables 3-5 Figures S4D and F). Remarkably, MYC-R + / Myc high GCB-DLBCL had a characteristic gene expression profiling in DLBCL.…”

Mechanisms of action of BCL6 during germinal center B cell development

“…This is evident by this fact that BCl6 binding sites are significantly coincident with the cistrome of these proteins including MYB (v-myb myeloblastosis viral oncogene homology), IRF8 (interferon-regulatory factor 8) and BACH2 [41,44,45]. BCL6 seems to antagonize or synergize these transcription factors in programing the GC phenotype.…”

“…BCL6 seems to antagonize or synergize these transcription factors in programing the GC phenotype. For instance, BCL6 cooperates with BACH2 to suppress PRDM1 transcription and terminal differentiation [45]. Finally, BCL6 may suppress transcription by competing for binding with STAT family transcriptional activators, which share quite similar binding sites with BCL6 [6,16,46].…”

“…For instance, BCL6 binding to the promoter of two genes (CDKN1A and BCL2) is dependent on ZBTB17 (also known as Miz1) [29,44]. BCL6 is recruited to the promoter of PRDM1 through BACH2 (BTB and CNC homologue 2) [45].…”

Let's give BACH2 a breath of fresh air

“…The activity BACH2 in normal cells is tightly regulated at different levels in a very dynamic way (see figure). 5 3 Heme regulates BACH2 at the protein level, both reducing its stability and decreasing its binding to DNA. [5][6][7] PI3K/AKT/mTOR-mediated phosphorylation of BACH2 leads to a decreased protein activity, changing its cellular localization from the nucleus to the cytoplasm.…”