Abstract
Treatment with anti-CD20 antibodies is only moderately efficient in chronic lymphocytic leukemia (CLL), a feature which has been explained by the inherently low CD20 expression in CLL. It has been shown that CD20 is epigenetically regulated and that histone deacetylase inhibitors (HDACis) can increase CD20 expression in vitro in CLL. To assess whether HDACis can upregulate CD20 also in vivo in CLL, the HDACi valproate was given to three del13q/NOTCH1wt CLL patients and CD20 levels were analysed (the PREVAIL study). Valproate treatment resulted in expected global activating histone modifications suggesting HDAC inhibitory effects. However, although valproate induced expression of CD20 mRNA and protein in the del13q/NOTCH1wt I83-E95 CLL cell line, no such effects were observed in the patients studied. In contrast to the cell line, in patients valproate treatment resulted in transient recruitment of the transcriptional repressor EZH2 to the CD20 promoter, correlating to an increase of the repressive histone mark H3K27me3. This suggests that valproate-mediated induction of CD20 may be hampered by EZH2 mediated H3K27me3 in vivo in CLL. Moreover, valproate treatment resulted in induction of EZH2 and global H3K27me3 in patient cells, suggesting transcriptionally repressive effects of valproate in CLL. Our results suggest new in vivo mechanisms of HDACis which may have implications on the design of future clinical trials in B-cell malignancies.
Highlights
Monoclonal antibodies targeting CD20 is one of the cornerstones in the treatment of B-cell malignancies
Downregulation of CD20 has been described in a number of case reports of patients with relapsed/refractory B-cell lymphoma who became unresponsive to rituximab-based therapies and is probably one of the most important factors contributing to rituximab-resistance [2, 3]
This suggests that inhibitors of HDACs (HDACis) could counteract rituximab-resistance, www.impactjournals.com/oncotarget and is consistent with the finding by our group that the histone deacetylase inhibitors (HDACis) valproate upregulates CD20 protein and mRNA expression in vivo in diffuse large B-cell lymphoma (DLBCL) patients [6]
Summary
Monoclonal antibodies targeting CD20 is one of the cornerstones in the treatment of B-cell malignancies. Tsai et al reported reduced CD20 promoter activity and a defect in CD20 transport as two novel mechanisms responsible for CD20 downregulation in rituximab-resistant cell lines [4]. Sugimoto and colleagues have shown escape from CD20 antibody treatment by CD20 downregulation mediated by recruitment of the Sin3AHDAC1 complex to the CD20 promoter in resistant B-cell lymphoma cell lines [5]. This suggests that inhibitors of HDACs (HDACis) could counteract rituximab-resistance, www.impactjournals.com/oncotarget and is consistent with the finding by our group that the HDACi valproate upregulates CD20 protein and mRNA expression in vivo in diffuse large B-cell lymphoma (DLBCL) patients [6]. Valproate induces CD20 expression and increases rituximab-induced CDC in a mouse model of B-cell lymphoma [7]
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