Genome-wide analysis of histone H3 acetylation patterns in AML identifies PRDX2 as an epigenetically silenced tumor suppressor gene

Shuchi Agrawal-Singh; Fabienne Isken; Konstantin Agelopoulos; Hans-Ulrich Klein; Nils H Thoennissen; Gabriele Koehler; Antje Hascher; Nicole Bäumer; Wolfgang E Berdel; Christian Thiede; Gerhard Ehninger; Anke Becker; Peter Schlenke; Yipeng Wang; Michael McClelland; Utz Krug; Steffen Koschmieder; Thomas Büchner; Dae-Yeul Yu; Shailendra Vikram Singh; Klaus Hansen; Hubert Serve; Martin Dugas; Carsten Müller-Tidow

doi:10.1182/blood-2011-06-358705

Genome-wide analysis of histone H3 acetylation patterns in AML identifies PRDX2 as an epigenetically silenced tumor suppressor gene

Shuchi Agrawal-Singh, Fabienne Isken, Konstantin Agelopoulos, Hans-Ulrich Klein, Nils H Thoennissen, Gabriele Koehler, Antje Hascher, Nicole Bäumer, Wolfgang E Berdel, Christian Thiede, Gerhard Ehninger, Anke Becker, Peter Schlenke, Yipeng Wang, Michael McClelland, Utz Krug, Steffen Koschmieder, Thomas Büchner, Dae-Yeul Yu, Shailendra Vikram SinghKlaus Hansen, Hubert Serve, Martin Dugas, Carsten Müller-Tidow

67 Citationer (Scopus)

Abstract

With the use of ChIP on microarray assays in primary leukemia samples, we report that acute myeloid leukemia (AML) blasts exhibit significant alterations in histone H3 acetylation (H3Ac) levels at > 1000 genomic loci compared with CD34(+) progenitor cells. Importantly, core promoter regions tended to have lower H3Ac levels in AML compared with progenitor cells, which suggested that a large number of genes are epigenetically silenced in AML. Intriguingly, we identified peroxiredoxin 2 (PRDX2) as a novel potential tumor suppressor gene in AML. H3Ac was decreased at the PRDX2 gene promoter in AML, which correlated with low mRNA and protein expression. We also observed DNA hypermethylation at the PRDX2 promoter in AML. Low protein expression of the antioxidant PRDX2 gene was clinically associated with poor prognosis in patients with AML. Functionally, PRDX2 acted as inhibitor of myeloid cell growth by reducing levels of reactive oxygen species (ROS) generated in response to cytokines. Forced PRDX2 expression inhibited c-Myc-induced leukemogenesis in vivo on BM transplantation in mice. Taken together, epigenome-wide analyses of H3Ac in AML led to the identification of PRDX2 as an epigenetically silenced growth suppressor, suggesting a possible role of ROS in the malignant phenotype in AML.

Originalsprog	Engelsk
Tidsskrift	Blood
Vol/bind	119
Udgave nummer	10
Sider (fra-til)	2346-57
Antal sider	12
ISSN	0006-4971
DOI	https://doi.org/10.1182/blood-2011-06-358705
Status	Udgivet - 8 mar. 2012

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10.1182/blood-2011-06-358705

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Agrawal-Singh, S., Isken, F., Agelopoulos, K., Klein, H.-U., Thoennissen, N. H., Koehler, G., Hascher, A., Bäumer, N., Berdel, W. E., Thiede, C., Ehninger, G., Becker, A., Schlenke, P., Wang, Y., McClelland, M., Krug, U., Koschmieder, S., Büchner, T., Yu, D.-Y., ... Müller-Tidow, C. (2012). Genome-wide analysis of histone H3 acetylation patterns in AML identifies PRDX2 as an epigenetically silenced tumor suppressor gene. Blood, 119(10), 2346-57. https://doi.org/10.1182/blood-2011-06-358705

Agrawal-Singh, S, Isken, F, Agelopoulos, K, Klein, H-U, Thoennissen, NH, Koehler, G, Hascher, A, Bäumer, N, Berdel, WE, Thiede, C, Ehninger, G, Becker, A, Schlenke, P, Wang, Y, McClelland, M, Krug, U, Koschmieder, S, Büchner, T, Yu, D-Y, Singh, SV, Hansen, K, Serve, H, Dugas, M & Müller-Tidow, C 2012, 'Genome-wide analysis of histone H3 acetylation patterns in AML identifies PRDX2 as an epigenetically silenced tumor suppressor gene', Blood, bind 119, nr. 10, s. 2346-57. https://doi.org/10.1182/blood-2011-06-358705

@article{94edda71d40443d9b6d206c54753a029,

title = "Genome-wide analysis of histone H3 acetylation patterns in AML identifies PRDX2 as an epigenetically silenced tumor suppressor gene",

abstract = "With the use of ChIP on microarray assays in primary leukemia samples, we report that acute myeloid leukemia (AML) blasts exhibit significant alterations in histone H3 acetylation (H3Ac) levels at > 1000 genomic loci compared with CD34(+) progenitor cells. Importantly, core promoter regions tended to have lower H3Ac levels in AML compared with progenitor cells, which suggested that a large number of genes are epigenetically silenced in AML. Intriguingly, we identified peroxiredoxin 2 (PRDX2) as a novel potential tumor suppressor gene in AML. H3Ac was decreased at the PRDX2 gene promoter in AML, which correlated with low mRNA and protein expression. We also observed DNA hypermethylation at the PRDX2 promoter in AML. Low protein expression of the antioxidant PRDX2 gene was clinically associated with poor prognosis in patients with AML. Functionally, PRDX2 acted as inhibitor of myeloid cell growth by reducing levels of reactive oxygen species (ROS) generated in response to cytokines. Forced PRDX2 expression inhibited c-Myc-induced leukemogenesis in vivo on BM transplantation in mice. Taken together, epigenome-wide analyses of H3Ac in AML led to the identification of PRDX2 as an epigenetically silenced growth suppressor, suggesting a possible role of ROS in the malignant phenotype in AML.",

keywords = "Acetylation, Acute Disease, Adolescent, Adult, Aged, Aged, 80 and over, Cell Proliferation, Cells, Cultured, DNA Methylation, Epigenesis, Genetic, Female, Gene Expression Profiling, Genome-Wide Association Study, HL-60 Cells, Histones, Humans, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Peroxiredoxins, Reactive Oxygen Species, Tumor Suppressor Proteins, U937 Cells, Young Adult",

author = "Shuchi Agrawal-Singh and Fabienne Isken and Konstantin Agelopoulos and Hans-Ulrich Klein and Thoennissen, {Nils H} and Gabriele Koehler and Antje Hascher and Nicole B{\"a}umer and Berdel, {Wolfgang E} and Christian Thiede and Gerhard Ehninger and Anke Becker and Peter Schlenke and Yipeng Wang and Michael McClelland and Utz Krug and Steffen Koschmieder and Thomas B{\"u}chner and Dae-Yeul Yu and Singh, {Shailendra Vikram} and Klaus Hansen and Hubert Serve and Martin Dugas and Carsten M{\"u}ller-Tidow",

year = "2012",

month = mar,

day = "8",

doi = "10.1182/blood-2011-06-358705",

language = "English",

volume = "119",

pages = "2346--57",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "10",

}

TY - JOUR

T1 - Genome-wide analysis of histone H3 acetylation patterns in AML identifies PRDX2 as an epigenetically silenced tumor suppressor gene

AU - Agrawal-Singh, Shuchi

AU - Isken, Fabienne

AU - Agelopoulos, Konstantin

AU - Klein, Hans-Ulrich

AU - Thoennissen, Nils H

AU - Koehler, Gabriele

AU - Hascher, Antje

AU - Bäumer, Nicole

AU - Berdel, Wolfgang E

AU - Thiede, Christian

AU - Ehninger, Gerhard

AU - Becker, Anke

AU - Schlenke, Peter

AU - Wang, Yipeng

AU - McClelland, Michael

AU - Krug, Utz

AU - Koschmieder, Steffen

AU - Büchner, Thomas

AU - Yu, Dae-Yeul

AU - Singh, Shailendra Vikram

AU - Hansen, Klaus

AU - Serve, Hubert

AU - Dugas, Martin

AU - Müller-Tidow, Carsten

PY - 2012/3/8

Y1 - 2012/3/8

N2 - With the use of ChIP on microarray assays in primary leukemia samples, we report that acute myeloid leukemia (AML) blasts exhibit significant alterations in histone H3 acetylation (H3Ac) levels at > 1000 genomic loci compared with CD34(+) progenitor cells. Importantly, core promoter regions tended to have lower H3Ac levels in AML compared with progenitor cells, which suggested that a large number of genes are epigenetically silenced in AML. Intriguingly, we identified peroxiredoxin 2 (PRDX2) as a novel potential tumor suppressor gene in AML. H3Ac was decreased at the PRDX2 gene promoter in AML, which correlated with low mRNA and protein expression. We also observed DNA hypermethylation at the PRDX2 promoter in AML. Low protein expression of the antioxidant PRDX2 gene was clinically associated with poor prognosis in patients with AML. Functionally, PRDX2 acted as inhibitor of myeloid cell growth by reducing levels of reactive oxygen species (ROS) generated in response to cytokines. Forced PRDX2 expression inhibited c-Myc-induced leukemogenesis in vivo on BM transplantation in mice. Taken together, epigenome-wide analyses of H3Ac in AML led to the identification of PRDX2 as an epigenetically silenced growth suppressor, suggesting a possible role of ROS in the malignant phenotype in AML.

AB - With the use of ChIP on microarray assays in primary leukemia samples, we report that acute myeloid leukemia (AML) blasts exhibit significant alterations in histone H3 acetylation (H3Ac) levels at > 1000 genomic loci compared with CD34(+) progenitor cells. Importantly, core promoter regions tended to have lower H3Ac levels in AML compared with progenitor cells, which suggested that a large number of genes are epigenetically silenced in AML. Intriguingly, we identified peroxiredoxin 2 (PRDX2) as a novel potential tumor suppressor gene in AML. H3Ac was decreased at the PRDX2 gene promoter in AML, which correlated with low mRNA and protein expression. We also observed DNA hypermethylation at the PRDX2 promoter in AML. Low protein expression of the antioxidant PRDX2 gene was clinically associated with poor prognosis in patients with AML. Functionally, PRDX2 acted as inhibitor of myeloid cell growth by reducing levels of reactive oxygen species (ROS) generated in response to cytokines. Forced PRDX2 expression inhibited c-Myc-induced leukemogenesis in vivo on BM transplantation in mice. Taken together, epigenome-wide analyses of H3Ac in AML led to the identification of PRDX2 as an epigenetically silenced growth suppressor, suggesting a possible role of ROS in the malignant phenotype in AML.

KW - Acetylation

KW - Acute Disease

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Cell Proliferation

KW - Cells, Cultured

KW - DNA Methylation

KW - Epigenesis, Genetic

KW - Female

KW - Gene Expression Profiling

KW - Genome-Wide Association Study

KW - HL-60 Cells

KW - Histones

KW - Humans

KW - Male

KW - Middle Aged

KW - Oligonucleotide Array Sequence Analysis

KW - Peroxiredoxins

KW - Reactive Oxygen Species

KW - Tumor Suppressor Proteins

KW - U937 Cells

KW - Young Adult

U2 - 10.1182/blood-2011-06-358705

DO - 10.1182/blood-2011-06-358705

M3 - Journal article

C2 - 22207736

SN - 0006-4971

VL - 119

SP - 2346

EP - 2357

JO - Blood

JF - Blood

IS - 10

ER -

Genome-wide analysis of histone H3 acetylation patterns in AML identifies PRDX2 as an epigenetically silenced tumor suppressor gene

Abstract

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