| Description |
Canonically, histone deacetylases (HDACs) have been described as regulators of transcription. Their removal of acetyl groups from histones leads to more compact chromatin and reduced levels of transcription. While HDACs are integral regulators of transcription, they also play a number of different roles in cellular processes such as splicing, mitosis, meiosis and replication. This array of processes has made HDACs an important therapeutic target, particularly in cancers where they are often misregulated. One malignancy that could be targeted with HDAC inhibition (HDI) is Diffuse Large B-cell Lymphoma (DLBCL). A significant number of patients with DLBCL harbor a gain-of-function mutation in the Enhancer of Zeste Homolog 2 (EZH2), which leads to hypermethylation of chromatin. As methylation and acetylation are mutually exclusive chromatin modifications at the same residue, the inhibition of HDACs can skew the balance at these sites towards acetylation. With increased acetylation these cancer cells have a modified transcriptome, but also exhibit impaired DNA repair. The impairment of DNA repair can lead to an accumulation of DNA damage and eventually cell death. An important tool in the evaluation of DNA damage and repair has been the utilization of micro-laser irradiation to create "lines" of damage within cells, but in the past this method has been limited to adherent cells, as cells need to be iv immobile during the irradiation process. A new variation on this method has been developed to immobilize suspension B-cells for micro-irradiation. Utilizing this method, it has been shown that HDI modulates histone modifications differently at sites of DNA damage when compared to global levels of the same modifiers. Given the effects of HDI on DNA damage and repair, another malignancy that may benefit from HDI is B-cell precursor acute lymphoblastic leukemia (Pre-B-ALL). A subset of Pre-B-ALL express the Philadelphia chromosome, a translocation between chromosomes 9 and 22 that produces the BCR-ABL1 oncogene. Studies have shown that the BCR-ABL1 oncoprotein can confer hyperactive DNA repair in these patients, leading to chemoresistance. After evaluation, treatment of Pre-B-ALL with HDAC inhibitor does indeed impair the DNA repair networks and helps to overcome the survival advantage conferred by BCR-ABL1. |
