The Effect of the Histone Deacetylase Inhibitor PXD101 on the Transcriptional Regulation of Diffuse Large B-Cell Lymphona

Abstract

Diffuse Large B-cell Lymphoma (DLBCL) is the most common type of adult lymphoma. With current treatments this disease is curable, but remains fatal for 30-40% of patients. DLBCL is an extremely heterogeneous disease, and the lack of understanding about its variations makes it difficult to determine a second line of treatment for patients who do not respond to standard chemotherapy. Histone deacetylase inhibitors (HDACI) have been shown to be effective against blood cancers. HDACIs are known to have transcriptional and non-transcriptional effects; however, little is understood about their complex functions. Some DLBCL cell lines have been shown to be growth sensitive, while others are resistant, to the HDACI PXD101. In order to better understand both DLBCL and the mechanisms of PXD101 action, transcription factor binding site overrepresentation analysis of gene expression profiling data was used to identify signaling pathways modulated by drug treatment. Cells resistant to PXD101 were transfected with reporter vectors designed to measure the activity of specific transcription factors. Studying the transcription factor NF-κB has proven that this technique is sufficient to detect changes in activity upon drug treatment, and that the transcription factors identified can be linked to biological pathways that help explain the phenotypic response observed.