BCL6

BCL6 (B-cell lymphoma 6) is a zinc-finger transcriptional repressor that plays a crucial role in the germinal center (GC) reaction of B cells. BCL6 can promote the continuous proliferation of B cells in the highly mutagenic GC environment by suppressing DNA damage checkpoint genes (ATR, CHEK1, TP53), thereby reducing the cellular response to DNA damage. Additionally, BCL6 facilitates B cell proliferation by downregulating cell cycle inhibitors (CDKN1A, PTEN) and prevents premature differentiation into plasma cells by repressing terminal differentiation genes (IRF4, PRDM1), ensuring the maintenance of the GC reaction. Furthermore, BCL6 competitively inhibits inflammatory signaling pathways (STAT3, NF-κB), thereby reducing excessive immune activation and exerting an anti-inflammatory effect.
The stable expression of BCL6 relies on positive feedback mechanisms, such as p300-mediated inhibition of HSP90 acetylation, which stabilizes BCL6, and EZH2-catalyzed H3K27 methylation, which further enhances BCL6's transcriptional repression. In various cancers, including diffuse large B-cell lymphoma (DLBCL), B-cell acute lymphoblastic leukemia (B-ALL), chronic myeloid leukemia (CML), breast cancer, and non-small cell lung cancer (NSCLC), BCL6 contributes to cancer cell survival through genetic mutations, chromosomal translocations, or dysregulation of co-repressors. Therefore, inhibitors targeting the BTB domain of BCL6 can effectively block its interaction with co-repressors, thereby suppressing tumor growth and providing a novel therapeutic strategy for malignant tumors^[1].