Profiling of histone H3 lysine 9 trimethylation levels predicts transcription factor activity and survival in acute myeloid leukemia
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Acute myeloid leukemia (AML) is commonly associated with alterations in transcription factors because of altered expression or gene mutations. These changes might induce leukemia-specific patterns of histone modifications. We used chromatin-immunoprecipitation on microarray to analyze histone 3 lysine 9 trimethylation (H3K9me3) patterns in primary AML (n = 108), acute lymphoid leukemia (n = 28), CD34+ cells (n = 21) and white blood cells (n = 15) specimens. Hundreds of promoter regions in AML showed significant alterations in H3K9me3 levels. H3K9me3 deregulation in AML occurred preferentially as a decrease in H3K9me3 levels at core promoter regions. The altered genomic regions showed an overrepresentation of cis-binding sites for ETS and cyclic adenosine monophosphate response elements (CREs) for transcription factors of the CREB/CREM/ATF1 family. The decrease in H3K9me3 levels at CREs was associated with increased CRE-driven promoter activity in AML blasts in vivo. AML-specific H3K9me3 patterns were not associated with known cytogenetic abnormalities. But a signature derived from H3K9me3 patterns predicted event-free survival in AML patients. When the H3K9me3 signature was combined with established clinical prognostic markers, it outperformed prognosis prediction based on clinical parameters alone. These findings demonstrate widespread changes of H3K9me3 levels at gene promoters in AML. Signatures of histone modification patterns are associated with patient prognosis in AML.
Date Issued
2010-11-04
Date Acceptance
2010-03-17
Citation
Blood, 2010, 116 (18), pp.3564-3571
ISSN
0006-4971
Publisher
American Society of Hematology (ASH Publications)
Start Page
3564
End Page
3571
Journal / Book Title
Blood
Volume
116
Issue
18
Copyright Statement
"This research was originally published in Blood. Carsten Müller-Tidow, Hans-Ulrich Klein, Antje Hascher, Fabienne Isken, Lara Tickenbrock, Nils Thoennissen, Shuchi Agrawal-Singh, Petra Tschanter, Christine Disselhoff, Yipeng Wang, Anke Becker, Christian Thiede, Gerhard Ehninger, Udo zur Stadt, Steffen Koschmieder, Matthias Seidl, Frank U. Müller, Wilhelm Schmitz, Peter Schlenke, Michael McClelland, Wolfgang E. Berdel, Martin Dugas, Hubert Serve, on behalf of the Study Alliance Leukemia; Profiling of histone H3 lysine 9 trimethylation levels predicts transcription factor activity and survival in acute myeloid leukemia. Blood 2010; 116 (18): 3564–3571. doi: https://doi.org/10.1182/blood-2009-09-240978. © the American Society of Hematology."
Identifier
10.1182/blood-2009-09-240978
Publication Status
Published
Date Publish Online
2010-05-24