Enhanced efficacy of a specific HDAC3 inhibitor in combination with 5-Azacitidine against diffuse large B-cell lymphoma [OCI_ly7_RNAseq_Day5]

Diffuse large B-cell lymphoma (DLBCL) refers to an aggressive lymphoma that arises from germinal center (GC) B-cells, which differentiate into plasma cells (PC) to produce high affinity antibodies. 40% of DLBCL patients 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) loss of acetylation of the lysine 27 of histone 3 (H3K27ac)-through recruitment of histone deacetylase 3 (HDAC3). Thus, we investigated the efficacy against DLBCL of the hypomethylating agent (HMA) 5-Azacitidine (5-Aza) and a specific HDAC3 inhibitor (HDAC3i).