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Myelodysplasias

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

Leukemia volume 26, pages 1804–1811 (2012)Cite this article

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Abstract

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.

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Acknowledgements

The major support of this work comes from the grant (investigators TS and MK) of the Ministry of Industry and Trade (FR-TI2/509). Other support is from Grants NS10310-3/2009, 2B06077, MSM 0021620806 PRVOUK, MSM 0021620808, LC06044, SVV-2011-262507 and SVV-2012, GAUK 251135 82210, GACR P305/12/1033, UNCE 204021. Collaborator's support comes from the Grants NS10632-3/2009, NS9634-4/2008, and Yorkshire Cancer Research (PL). We thank Drs Ulrich Steidl and Daniel Tenen for providing us with the mouse model of PU.1low AML. We are very thankful to all MDS patients participating in this study.

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Author notes

  1. N Curik, P Burda, K Vargova and V Pospisil: These authors contributed equally to this work.

  2. P Laslo, A Jonasova and T Stopka: These authors are senior co-authors.

Authors and Affiliations

  1. First Faculty of Medicine, Institute of pathologic physiology, Charles University, Prague, Czech Republic

    N Curik, P Burda, K Vargova, V Pospisil, P Vlckova, F Savvulidi, E Necas, M Trneny, A Jonasova & T Stopka

  2. Institute of Hematology and Blood Transfusion, Prague, Czech Republic

    M Belickova, H Hajkova, C Haskovec, J Cermak & M Trneny

  3. KRD and CEBIOS, Prague, Czech Republic

    M Krivjanska

  4. First Medical Department—Hematology, General Faculty Hospital, Prague, Czech Republic

    M Trneny, A Jonasova & T Stopka

  5. University of Leeds, Leeds, UK

    P Laslo

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Curik, N., Burda, P., Vargova, K. et al. 5-Azacitidine in aggressive myelodysplastic syndromes regulates chromatin structure at PU.1 gene and cell differentiation capacity. Leukemia 26, 1804–1811 (2012). https://doi.org/10.1038/leu.2012.47

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