Profiling of histone H3 lysine 9 trimethylation levels predicts transcription factor activity and survival in acute myeloid leukemia.
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.
Müller-Tidow
Carsten
C
Department of Medicine A, Hematology, Oncology and Pneumology, Interdisciplinary Center for Clinical Research, University of Münster, Münster, Germany.
Klein
Hans-Ulrich
HU
Hascher
Antje
A
Isken
Fabienne
F
Tickenbrock
Lara
L
Thoennissen
Nils
N
Agrawal-Singh
Shuchi
S
Tschanter
Petra
P
Disselhoff
Christine
C
Wang
Yipeng
Y
Becker
Anke
A
Thiede
Christian
C
Ehninger
Gerhard
G
zur Stadt
Udo
U
Koschmieder
Steffen
S
Seidl
Matthias
M
Müller
Frank U
FU
Schmitz
Wilhelm
W
Schlenke
Peter
P
McClelland
Michael
M
Berdel
Wolfgang E
WE
Dugas
Martin
M
Serve
Hubert
H
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
D018952:Antigens, CD34; D006657:Histones; D014157:Transcription Factors; D008239:Lysine