title: Profiling of histone H3 lysine 9 trimethylation levels predicts transcription factor activity and survival in acute myeloid leukemia.
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.
authors.affiliation: Department of Medicine A, Hematology, Oncology and Pneumology, Interdisciplinary Center for Clinical Research, University of Münster, Münster, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Klein
authors.forename: Antje
authors.initials: A
authors.lastname: Hascher
authors.forename: Fabienne
authors.initials: F
authors.lastname: Isken
authors.forename: Lara
authors.initials: L
authors.lastname: Tickenbrock
authors.forename: Nils
authors.initials: N
authors.lastname: Thoennissen
authors.forename: Shuchi
authors.initials: S
authors.lastname: Agrawal-Singh
authors.forename: Petra
authors.initials: P
authors.lastname: Tschanter
authors.forename: Christine
authors.initials: C
authors.lastname: Disselhoff
authors.forename: Yipeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Anke
authors.initials: A
authors.lastname: Becker
authors.forename: Christian
authors.initials: C
authors.lastname: Thiede
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
authors.forename: Udo
authors.initials: U
authors.lastname: zur Stadt
authors.forename: Steffen
authors.initials: S
authors.lastname: Koschmieder
authors.forename: Matthias
authors.initials: M
authors.lastname: Seidl
authors.forename: Frank U
authors.initials: FU
authors.lastname: Müller
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Schmitz
authors.forename: Peter
authors.initials: P
authors.lastname: Schlenke
authors.forename: Michael
authors.initials: M
authors.lastname: McClelland
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.forename: Martin
authors.initials: M
authors.lastname: Dugas
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
mesh_terms: D000293:Adolescent; D018952:Antigens, CD34 / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008297:Male; D008745:Methylation; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D018952:Antigens, CD34; D006657:Histones; D014157:Transcription Factors; D008239:Lysine