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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

Scialdone, Annarita LU ; Hasni, Muhammad Sharif LU ; Damm, Jesper Kofoed LU ; Lennartsson, Andreas LU ; Gullberg, Urban LU and Drott, Kristina LU (2017) In Oncotarget 8(23). p.37409-37422
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... (More)

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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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
CD20, Chronic lymphocytic leukemia, EZH2, H3K27me3, Valproate
in
Oncotarget
volume
8
issue
23
pages
14 pages
publisher
Impact Journals, LLC
external identifiers
  • scopus:85020188733
  • wos:000403236400042
ISSN
1949-2553
DOI
10.18632/oncotarget.16964
language
English
LU publication?
yes
id
40882298-53b6-4ed8-985a-46365119e329
date added to LUP
2017-08-22 12:03:08
date last changed
2017-09-18 11:42:35
@article{40882298-53b6-4ed8-985a-46365119e329,
  abstract     = {<p>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.</p>},
  author       = {Scialdone, Annarita and Hasni, Muhammad Sharif and Damm, Jesper Kofoed and Lennartsson, Andreas and Gullberg, Urban and Drott, Kristina},
  issn         = {1949-2553},
  keyword      = {CD20,Chronic lymphocytic leukemia,EZH2,H3K27me3,Valproate},
  language     = {eng},
  number       = {23},
  pages        = {37409--37422},
  publisher    = {Impact Journals, LLC},
  series       = {Oncotarget},
  title        = {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},
  url          = {http://dx.doi.org/10.18632/oncotarget.16964},
  volume       = {8},
  year         = {2017},
}