Therapeutic targeting of the BCL6 oncogene for diffuse large B-cell lymphomas

Panel A: During normal B-cell maturation, activated B-cells form germinal centers (GC) (shaded circle) in order to form high affinity antibodies. Mature B-cells first become centroblasts, highly proliferating cells in which BCL6 expression is induced. These cells form the dark zone of the GC. Pictured below the centroblast cell is a representation of BCL6 and its three domains, the BTB, RD2 and Zinc fingers. BCL6 contributes to the centroblast phenotype by directly repressing the ATR, CHEK1, TP53 and CDKN1A genes through its BTB domain in order to facilitate proliferation and survival during class switch recombination and somatic hypermutation. BCL6 also represses the PRDM1 gene mostly through its second repression domain in order to block further differentiation. Centroblasts eventually migrate to a more heterogeneous area of the GC called the light zone where they encounter T-cells and follicular dendritic cells (FDC). CD40 signaling by T-cells can block the function of the BCL6 BTB domain by blocking its association with N-CoR and thus de-repress checkpoint genes. This presumably allows B cells damaged during affinity maturation to be weeded out (an apoptotic B-cell is pictured attached to a T-cells). Repression of PRDM1 is independent of the BTB domain, which allows B-cells to sustained blockade of PRDM1 and thus prevents premature differentiation. When CD40 signaling is transient these effects are reversible so that B-cells could maintain the centroblast phenotype and undergo further rounds of affinity maturation. More sustained CD40 signaling can induce IRF4 mediated repression of BCL6 and facilitate terminal differentiation of GC B cells selected by the FDCs into plasma cells or memory cells. GC B cells that have reached this stage in the light zone are called centrocytes. BCL6 can also be downregulated through the ATM pathway via proteolytic degradation when genomic damage reaches a critical level in B-cells. Panel B: Translocations or point mutations of the BCL6 locus can cause it to be expression constitutively and contribute to malignant transformation. Exposure of DLBCL cells to BPI can block the repressor effect of the BCL6 BTB domain and induce expression of ATR, CHEK1, TP53 and CDKN1A resulting in cell death. Downregulation of MTA3 can block the repressor effect of the RD2 and induce PRDM1 resulting in differentiation.

Publication

Therapeutic targeting of the BCL6 oncogene for diffuse large B-cell lymphomas. () Samir S Parekh, et al. Leuk Lymphoma. ;49(5):874-882. Figure: F1. Homo sapiens

Disease mentions