Oncotarget

Research Papers:

The HDAC inhibitor valproate induces a bivalent status of the CD20 promoter in CLL patients suggesting distinct epigenetic regulation of CD20 expression in CLL in vivo

Annarita Scialdone, Muhammad Sharif Hasni, Jesper Kofoed Damm, Andreas Lennartsson, Urban Gullberg and Kristina Drott _

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Oncotarget. 2017; 8:37409-37422. https://doi.org/10.18632/oncotarget.16964

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Abstract

Annarita Scialdone1, Muhammad Sharif Hasni1, Jesper Kofoed Damm1, Andreas Lennartsson2, Urban Gullberg1, Kristina Drott1,3

1Department of Hematology and Transfusion Medicine, Lund University, Lund, Sweden

2Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden

3Clinic of Oncology, Skåne University Hospital, Lund, Sweden

Correspondence to:

Kristina Drott, email: [email protected]

Keywords: valproate, chronic lymphocytic leukemia, H3K27me3, CD20, EZH2

Received: December 21, 2016     Accepted: March 08, 2017     Published: April 08, 2017

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.


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