HDAC3 inhibitors: a potential treatment for non-Hodgkin lymphomas?

A study has identified histone deacetylase 3 (HDAC3) inhibitors are a possible novel therapy for both follicular lymphoma and diffuse large B-cell lymphomas (DLBCL) with cAMP-response element binding protein (CREBBP) mutations.

Researchers from the University of Texas MD Anderson Cancer Center, US, worked from previous research showing CREBBP mutations are common in both follicular lymphoma and DLBCL. CREBBP encodes a protein that alters the expression of genes by modifying the histone proteins around which DNA is wrapped.

“CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein,” said Dr Michael Green, assistant professor of Lymphoma and Myeloma at MD Anderson.” We showed that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome.”

Using CRISPR-Cas9 gene editing in murine models, the research team showed that HDAC3 selective inhibitors reverse aberrant epigenetic programming caused by CREBBP, inhibiting the growth of lymphoma cells and restoring immune cancer surveillance.

“Our study characterised the molecular consequences of CREBBP mutations and identified key cellular pathways silenced as a result of unopposed HDAC3 activity,” said Green. “We demonstrated how inhibition of HDAC3 restores these pathways, suppressing growth and most critically enabling T cells to recognise and kill lymphoma cells.”

The research, published in Cancer Discovery, suggests that HDAC3 inhibitors affect the expression of major histocompatibility molecular class II (MHC class II). MHC class II molecules are antigen presentation proteins, crucial for initiating adaptive immune responses.

“The frequency of MHC class II loss in DLBCL exceeds the frequency of CREBBP mutations in this disease through unknown mechanisms,” said Green. “The ability of HDAC3 inhibition to induce MHC class II expression may have potentially broad implications for immunotherapy. We believe that inhibition of HDAC3 represents a novel mechanism-based immune-epigenetic therapy for CREBBP- mutant lymphomas.”