5-azacitidine in aggressive myelodysplastic syndromes regulates chromatin structure at PU.1 gene and cell differentiation capacity
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
22343522
DOI
10.1038/leu.2012.47
PII: leu201247
Knihovny.cz E-resources
- MeSH
- Transcriptional Activation drug effects MeSH
- Azacitidine pharmacology therapeutic use MeSH
- Cell Differentiation drug effects genetics MeSH
- Chromatin genetics MeSH
- Colony-Stimulating Factors pharmacology MeSH
- Middle Aged MeSH
- Humans MeSH
- DNA Methylation drug effects MeSH
- Myelodysplastic Syndromes drug therapy genetics MeSH
- Cell Line, Tumor MeSH
- Neoplastic Stem Cells cytology drug effects metabolism MeSH
- Antimetabolites, Antineoplastic pharmacology therapeutic use MeSH
- Proto-Oncogene Proteins genetics metabolism MeSH
- Gene Expression Regulation, Leukemic drug effects MeSH
- Regulatory Sequences, Nucleic Acid drug effects MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Trans-Activators genetics metabolism MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Azacitidine MeSH
- Chromatin MeSH
- Colony-Stimulating Factors MeSH
- Antimetabolites, Antineoplastic MeSH
- proto-oncogene protein Spi-1 MeSH Browser
- Proto-Oncogene Proteins MeSH
- Trans-Activators MeSH
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.
References provided by Crossref.org
Combined Approach to Leukemic Differentiation Using Transcription Factor PU.1-Enhancing Agents
Analysis of 5-Azacytidine Resistance Models Reveals a Set of Targetable Pathways
Epigenetic control of SPI1 gene by CTCF and ISWI ATPase SMARCA5
