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5-azacitidine in aggressive myelodysplastic syndromes regulates chromatin structure at PU.1 gene and cell differentiation capacity

Nikola Curik, Pavel Burda, Karin Vargova, Vit Pospisil, Monika Belickova, Petra Vlckova, Filipp Savvulidi, Emanuel Necas, Hana Hajkova, Cedrik Haskovec, Jaroslav Cermak, Maria Krivjanska, Marek Trneny, Peter Laslo, Anna Jonasova, Tomas Stopka

. 2012 ; 26 (8) : 1804-1811.

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc13000946

Grantová podpora
NS9634 MZ0 CEP - Centrální evidence projektů
NS10310 MZ0 CEP - Centrální evidence projektů
NS10632 MZ0 CEP - Centrální evidence projektů

Epigenetic 5-azacitidine (AZA) therapy of high-risk myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) represents a promising, albeit not fully understood, approach. Hematopoietic transcription factor PU.1 is dynamically regulated by upstream regulatory element (URE), whose deletion causes downregulation of PU.1 leading to AML in mouse. In this study a significant group of the high-risk MDS patients, as well as MDS cell lines, displayed downregulation of PU.1 expression within CD34+ cells, which was associated with DNA methylation of the URE. AZA treatment in vitro significantly demethylated URE, leading to upregulation of PU.1 followed by derepression of its transcriptional targets and onset of myeloid differentiation. Addition of colony-stimulating factors (CSFs; granulocyte-CSF, granulocyte-macrophage-CSF and macrophage-CSF) modulated AZA-mediated effects on reprogramming of histone modifications at the URE and cell differentiation outcome. Our data collectively support the importance of modifying the URE chromatin structure as a regulatory mechanism of AZA-mediated activation of PU.1 and induction of the myeloid program in MDS.

Citace poskytuje Crossref.org

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