Defining cellular responses to HDAC-selective inhibitors reveals that efficient targeting of HDAC3 is required to elicit cytotoxicity and overcome naïve resistance to pan-HDACi in diffuse large B cell lymphoma.

Approved histone deacetylase (HDAC) inhibitors have low efficacy against the most commonly-diagnosed non-Hodgkin lymphoma, diffuse large B cell lymphoma (DLBCL), but the mechanisms underlying clinical resistance are poorly understood. Using a DLBCL cell-based model, we previously demonstrated that resistance to pan-HDAC inhibitors (HDACi) is characterized by reversible growth arrest and sensitivity by mitotic arrest and apoptosis. The goal of the current study is to better define mechanisms of sensitivity and resistance to the cytotoxic effects of HDACi by using HDAC-selective inhibitors to determine which HDACs need to be targeted to achieve the sensitive and resistant phenotypes.