5-Azacitidine in aggressive myelodysplastic syndromes regulates chromatin structure at PU.1 gene and cell differentiation capacity
| Autor: | Anna Jonasova, Krivjanska M, Marek Trneny, Monika Belickova, Emanuel Necas, Karina Vargova, Filipp Savvulidi, Nikola Curik, Hana Hájková, Petra Vlckova, Pospisil, Cedrik Haškovec, Pavel Burda, Tomas Stopka, Jaroslav Cermak, Peter Laslo |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Transcriptional Activation Antimetabolites Antineoplastic Cancer Research Cellular differentiation Azacitidine Regulatory Sequences Nucleic Acid Biology Colony-Stimulating Factors Cell Line Tumor Proto-Oncogene Proteins medicine Humans Gene Aged Aged 80 and over Genetics Gene Expression Regulation Leukemic Myelodysplastic syndromes Cell Differentiation Hematology DNA Methylation Middle Aged medicine.disease Chromatin Oncology Myelodysplastic Syndromes Neoplastic Stem Cells Trans-Activators Cancer research Female medicine.drug |
| Zdroj: | Leukemia. 26:1804-1811 |
| ISSN: | 1476-5551 0887-6924 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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