Targeting BCL-6:p53 Axis in Diffuse Large B-Cell Lymphoma

Understanding of the molecular pathogenesis of lymphoma has led to paradigm changing treatment opportunities. Gene expression profiling has defined three distinct subtypes of diffuse large B-cell lymphoma (DLBCL), including: (1) the GC subtype driven by the oncogene BCl-6; (2) the ABC subtype which is addicted to NF-kB, and seems to be enriched for cells addicted to the B-cell receptor (BCR); and (3) and type three or primary mediastinal lymphoma. In GC DLBCL there is a critical inverse relationship between Bcl-6 and p53, the functional status of which is linked to each transcription factor’s degree of acetylation. Deacetylation of Bcl-6 is required for its transcriptional repressor effects allowing for the oncogene to drive lymphomagenesis. Conversely, acetylation of p53 is activating, while class III HDACs, or sirtuins, are inhibited by agents such as niacinamide. One therapeutic strategy for lymphomas addicted to Bcl-6 over-expression is the pharmacologic modification of Bcl-6 and p53 using HDAC inhibitors. Classically, HDAC inhibitors are thought to lead to the accumulation of acetylated histone, which helps maintain chromatin in an open, transcritpionally active state.