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Profiling of histone H3 lysine 9 trimethylation levels predicts transcription factor activity and survival in acute myeloid leukemia

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 and Hubert Serve

Abstract

Acute Myeloid Leukemia (AML) is commonly associated with alterations in transcription factors due to altered expression or gene mutations. These changes might induce leukemia- specific patterns of histone modifications. We used ChIP-Chip to analyze histone H3 Lysine 9 trimethylation (H3K9me3) patterns in primary AML (n=109), ALL (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 c-AMP 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.

  • Submitted September 9, 2009.
  • Accepted March 17, 2010.