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C/EBP alpha and PU.1 are involved in distinct differentiation responses of acute promyelocytic leukemia HL-60 and NB4 cells via chromatin remodeling
Institute for Biochemistry, Vilnius, Lithuania .
Institute for Biochemistry, Vilnius, Lithuania .
Institute for Biochemistry, Vilnius, Lithuania .
State Research Institute Centre Innovat Med, Vilnius, Lithuania .
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2011 (English)In: DIFFERENTIATION, ISSN 0301-4681, Vol. 81, no 1, 57-67 p.Article in journal (Refereed) Published
Abstract [en]

C/EBP alpha and PU.1 are the basic transcription factors that control differentiation-related genes, including granulocyte- colony-stimulating factor (G-CSFR) and human neutrophil elastase (HNE). Here, we analyzed a role of C/EBP alpha and PU.1 in human acute leukemia cell lines, HL-60 and NB4, in association with a modified chromatin structure by histone deacetylase inhibitors, FK228, sodium phenyl butyrate and vitamin B3. We found that sodium phenyl butyrate alone and 6 h-pretreatment with phenyl butyrate or FK228 before the induction of differentiation with all-trans-retinoic acid in the presence of vitamin B3 effectively accelerated and enhanced differentiation to granulocytes in HL-60 but not in NB4 cells as detected by NBT test and the expression of CD11b and CD114 (G-CSFR) using flow cytometric analysis. HDACIs induced a time- and dose-dependent accumulation of hyper-acetylated histone H4 in both cell lines with the delay in NB4 cells. Time-dependent different induction of HL-60 and NB4 cell differentiation was paralleled by the activation of C/EBP alpha and PU.1 binding to the G-CSFR and the HNE promoters in electrophoretic mobility shift assay. Chromatin immunoprecipitation analysis revealed histone H4 acetylation in the G-CSF receptor promoter at the C/EBP alpha binding site in HL-60 but not in NB4 cells under the combined treatment. The results indicate that epigenetic events, such as histone acetylation, are involved in the activity modulation of the key transcription factors responsible for the induction of granulocytic differentiation in promyelocytic leukemia cells.

Place, publisher, year, edition, pages
Keyword [en]
Leukemia, Differentiation, Histone deacetylase inhibitors, Transcription factors
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-63396DOI: 10.1016/j.diff.2010.08.003ISI: 000284826700007OAI: diva2:379147
Available from: 2010-12-17 Created: 2010-12-17 Last updated: 2010-12-17

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Magnusson, Karl-Eric
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Medical Microbiology Faculty of Health Sciences
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