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; Hubert Serve

doi:10.1182/blood-2009-09-240978

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 McClellandWolfgang E Berdel, Martin Dugas, Hubert Serve

74 Citations (Scopus)

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.

Original language	English
Journal	Blood
ISSN	0006-4971
DOIs	https://doi.org/10.1182/blood-2009-09-240978
Publication status	Published - 4 Nov 2010

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Müller-Tidow, C., Klein, H-U., Hascher, A., Isken, F., Tickenbrock, L., Thoennissen, N., Agrawal-Singh, S., Tschanter, P., Disselhoff, C., Wang, Y., Becker, A., Thiede, C., Ehninger, G., Zur Stadt, U., Koschmieder, S., Seidl, M., Müller, F. U., Schmitz, W., Schlenke, P., ... Serve, H. (2010). Profiling of histone H3 lysine 9 trimethylation levels predicts transcription factor activity and survival in acute myeloid leukemia. Blood. https://doi.org/10.1182/blood-2009-09-240978

Müller-Tidow, C, Klein, H-U, Hascher, A, Isken, F, Tickenbrock, L, Thoennissen, N, Agrawal-Singh, S, Tschanter, P, Disselhoff, C, Wang, Y, Becker, A, Thiede, C, Ehninger, G, Zur Stadt, U, Koschmieder, S, Seidl, M, Müller, FU, Schmitz, W, Schlenke, P, McClelland, M, Berdel, WE, Dugas, M & Serve, H 2010, 'Profiling of histone H3 lysine 9 trimethylation levels predicts transcription factor activity and survival in acute myeloid leukemia', Blood. https://doi.org/10.1182/blood-2009-09-240978

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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.",

author = "Carsten M{\"u}ller-Tidow and Hans-Ulrich Klein and Antje Hascher and Fabienne Isken and Lara Tickenbrock and Nils Thoennissen and Shuchi Agrawal-Singh and Petra Tschanter and Christine Disselhoff and Yipeng Wang and Anke Becker and Christian Thiede and Gerhard Ehninger and {Zur Stadt}, Udo and Steffen Koschmieder and Matthias Seidl and M{\"u}ller, {Frank U} and Wilhelm Schmitz and Peter Schlenke and Michael McClelland and Berdel, {Wolfgang E} and Martin Dugas and Hubert Serve",

year = "2010",

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doi = "10.1182/blood-2009-09-240978",

language = "English",

journal = "Blood",

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T1 - Profiling of histone H3 lysine 9 trimethylation levels predicts transcription factor activity and survival in acute myeloid leukemia

AU - Müller-Tidow, Carsten

AU - Klein, Hans-Ulrich

AU - Hascher, Antje

AU - Isken, Fabienne

AU - Tickenbrock, Lara

AU - Thoennissen, Nils

AU - Agrawal-Singh, Shuchi

AU - Tschanter, Petra

AU - Disselhoff, Christine

AU - Wang, Yipeng

AU - Becker, Anke

AU - Thiede, Christian

AU - Ehninger, Gerhard

AU - Zur Stadt, Udo

AU - Koschmieder, Steffen

AU - Seidl, Matthias

AU - Müller, Frank U

AU - Schmitz, Wilhelm

AU - Schlenke, Peter

AU - McClelland, Michael

AU - Berdel, Wolfgang E

AU - Dugas, Martin

AU - Serve, Hubert

PY - 2010/11/4

Y1 - 2010/11/4

N2 - 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.

AB - 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.

U2 - 10.1182/blood-2009-09-240978

DO - 10.1182/blood-2009-09-240978

M3 - Journal article

C2 - 20498303

SN - 0006-4971

JO - Blood

JF - Blood

ER -

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

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