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The HDAC Inhibitor Givinostat Modulates the Hematopoietic Transcription Factors NFE2 and C-MYB in JAK2V617F Myeloproliferative Neoplasm Cells.
MedLine Citation:
PMID:  22579713     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
We investigated the mechanism of action of the HDAC inhibitor Givinostat (GVS) in JAK2(V617F) myeloproliferative neoplasm (MPN) cells. GVS inhibited colony formation and proliferation and induced apoptosis at doses 2-3 fold lower in a panel of JAK2(V617F) MPN compared to JAK2 wild type myeloid leukemia cell lines. By global gene expression analysis, we observed that at 6 hour GVS modulated 293 common genes in the JAK2(V617F) cell lines HEL and UKE1, of which 19 are implicated in cell cycle regulation and 33 in hematopoiesis. In particular, the hematopoietic transcription factors NFE2 and C-MYB were downmodulated by the drug specifically in JAK2(V617F) cells at both the RNA and protein level. GVS also inhibited JAK2-STAT5-ERK1/2 phosphorylation, but modulation of NFE2 and C-MYB was JAK2-independent, as shown using the JAK2 inhibitor TG101209. Indeed GVS had a direct effect on the NFE2 promoters, as demonstrated by specific enrichment of associated histone H3 acetylated at Lysine 9. Modulation by GVS of NFE2 was also observed in freshly isolated CD34(+) cells from MPN patients, and was accompanied by inhibition of their proliferation and differentiation towards the erythroid lineage. We conclude that GVS acts on MPN cells through dual JAK2-STAT5-ERK1/2 inhibition and downmodulation of NFE2 and C-MYB transcription.
Authors:
Ariel Amaru Calzada; Katia Todoerti; Luca Donadoni; Anna Pellicioli; Giacomo Tuana; Raffaella Gatta; Antonino Neri; Guido Finazzi; Roberto Mantovani; Alessandro Rambaldi; Martino Introna; Luigia Lombardi; Josée Golay
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-5-8
Journal Detail:
Title:  Experimental hematology     Volume:  -     ISSN:  1873-2399     ISO Abbreviation:  -     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-5-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0402313     Medline TA:  Exp Hematol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.
Affiliation:
USC Hematology, Ospedali Riuniti, Bergamo, Italy.
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