Enhanced efficacy of a specific HDAC3 inhibitor in combination with 5-azacitidine against diffuse large B-cell...

Diffuse large B-cell lymphoma (DLBCL) refers to an aggressive lymphoma that arises from germinal center (GC) B cells, which differentiate into plasma cells to produce high-affinity antibodies. A total of 40% of patients with DLBCL relapse or are refractory to the conventional immunochemotherapy treatment, usually with fatal consequences. DLBCL is characterized by profound alterations in the epigenome, which is correlated with poor survival. The abnormal epigenetic landscape of DLBCL tumors is associated with a blockade in GC exit and differentiation programs, which are regulated by the transcription factor BCL6. This aberrant repression of BCL6 target genes is mediated by (1) increased DNA methylation and (2) the loss of acetylation of lysine 27 of histone 3 through the recruitment of histone deacetylase 3 (HDAC3). Therefore, we investigated the efficacy of the hypomethylating agent 5-azacitidine (5-aza) and a specific HDAC3 inhibitor (HDAC3i) against DLBCL. We found that the treatment of activated B cell-like and GC B cell-like DLBCL cells with 5-aza plus HDAC3i had a potent synergistic antitumor activity in vitro and in vivo, which was superior to the effect of each single drug or 5-aza combined with nonspecific HDACi and, importantly, was not associated with toxicity in normal T cells. We also demonstrated that, compared with that with each drug used as single agents, the combined 5-aza and HDAC3i treatment induced the epigenetic remodeling of DLBCL cells, which resulted in a more potent reexpression of differentiation genes, including XBP1 and ATF4. Our results highlight the importance of specifically targeting multiple layers of the epigenome to maximize the efficacy of epigenetic-based therapies.