Increased HDAC1 deposition at hematopoietic promoters in AML and its association with patient survival

Lara Tickenbrock; Hans-Ulrich Klein; Cristina Trento; Antje Hascher; Stefanie Göllner; Nicole Bäumer; Robert Kuss; Shuchi Agrawal; Gesine Bug; Hubert Serve; Christian Thiede; Gerhard Ehninger; Udo Zur Stadt; Michael McClelland; Yipeng Wang; Anke Becker; Steffen Koschmieder; Wolfgang E Berdel; Martin Dugas; Carsten Müller-Tidow; Study Alliance Leukemia Group

doi:10.1016/j.leukres.2010.11.006

Increased HDAC1 deposition at hematopoietic promoters in AML and its association with patient survival

Lara Tickenbrock, Hans-Ulrich Klein, Cristina Trento, Antje Hascher, Stefanie Göllner, Nicole Bäumer, Robert Kuss, Shuchi Agrawal, Gesine Bug, Hubert Serve, Christian Thiede, Gerhard Ehninger, Udo Zur Stadt, Michael McClelland, Yipeng Wang, Anke Becker, Steffen Koschmieder, Wolfgang E Berdel, Martin Dugas, Carsten Müller-TidowStudy Alliance Leukemia Group

18 Citations (Scopus)

Abstract

Epigenetic changes play a crucial role in leukemogenesis. HDACs are frequently recruited to target gene promoters by balanced translocation derived oncogenic fusion proteins. As important epigenetic effector mechanisms, histone deacetylases (HDAC) have emerged as potential therapeutic targets. However, the patterns of HDAC1 localization and the role of HDACs in leukemia pathogenesis remain to be elucidated. Using ChIP-Chip analyses we analyzed HDAC1 deposition patterns at more than 10,000 gene promoters in a large cohort of leukemia patients and CD34+ controls. HDAC1 binding was significantly increased in AML blasts compared to CD34+ progenitor cells at 130 gene promoters whereas decreased binding was observed at 66 gene promoters. Distinct HDAC1 binding patterns occurred in AML subtypes with balanced translocations t(15;17), t(8;21) and inv(16). In addition, a more generalized signature was established, that revealed an AML specific pattern of HDAC1 distribution. Many of the HDAC1-binding altered promoters regulate genes involved in hematopoiesis, transcriptional regulation and signal transduction. HDAC1 binding patterns were associated with patients' event free survival. This is the first study to determine HDAC1 modification patterns in a large number of AML and ALL specimens. Our findings suggest that dyslocalization of HDAC1 is a common feature in AML. Importantly, HDAC1 modifications possess prognostic power for patient survival. Our findings suggest that altered HDAC1 localization is an explanation for the observed benefit of HDAC inhibitors in AML therapy.

Original language	English
Journal	Leukemia Research
Volume	35
Issue number	5
Pages (from-to)	620-5
Number of pages	6
ISSN	0145-2126
DOIs	https://doi.org/10.1016/j.leukres.2010.11.006
Publication status	Published - 1 May 2011

Keywords

Adolescent
Adult
Aged
Child
Child, Preschool
Chromatin
Female
Hematopoiesis
Histone Deacetylase 1
Humans
Infant
Leukemia, Myeloid, Acute
Male
Middle Aged
Prognosis
Promoter Regions, Genetic
Protein Binding
Survival Analysis
Tumor Markers, Biological
Young Adult

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10.1016/j.leukres.2010.11.006

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Tickenbrock, L., Klein, H-U., Trento, C., Hascher, A., Göllner, S., Bäumer, N., Kuss, R., Agrawal, S., Bug, G., Serve, H., Thiede, C., Ehninger, G., Stadt, U. Z., McClelland, M., Wang, Y., Becker, A., Koschmieder, S., Berdel, W. E., Dugas, M., ... Study Alliance Leukemia Group (2011). Increased HDAC1 deposition at hematopoietic promoters in AML and its association with patient survival. Leukemia Research, 35(5), 620-5. https://doi.org/10.1016/j.leukres.2010.11.006

Tickenbrock, L, Klein, H-U, Trento, C, Hascher, A, Göllner, S, Bäumer, N, Kuss, R, Agrawal, S, Bug, G, Serve, H, Thiede, C, Ehninger, G, Stadt, UZ, McClelland, M, Wang, Y, Becker, A, Koschmieder, S, Berdel, WE, Dugas, M, Müller-Tidow, C & Study Alliance Leukemia Group 2011, 'Increased HDAC1 deposition at hematopoietic promoters in AML and its association with patient survival', Leukemia Research, vol. 35, no. 5, pp. 620-5. https://doi.org/10.1016/j.leukres.2010.11.006

@article{57440071c8b64fdabdf0b06431013d94,

title = "Increased HDAC1 deposition at hematopoietic promoters in AML and its association with patient survival",

abstract = "Epigenetic changes play a crucial role in leukemogenesis. HDACs are frequently recruited to target gene promoters by balanced translocation derived oncogenic fusion proteins. As important epigenetic effector mechanisms, histone deacetylases (HDAC) have emerged as potential therapeutic targets. However, the patterns of HDAC1 localization and the role of HDACs in leukemia pathogenesis remain to be elucidated. Using ChIP-Chip analyses we analyzed HDAC1 deposition patterns at more than 10,000 gene promoters in a large cohort of leukemia patients and CD34+ controls. HDAC1 binding was significantly increased in AML blasts compared to CD34+ progenitor cells at 130 gene promoters whereas decreased binding was observed at 66 gene promoters. Distinct HDAC1 binding patterns occurred in AML subtypes with balanced translocations t(15;17), t(8;21) and inv(16). In addition, a more generalized signature was established, that revealed an AML specific pattern of HDAC1 distribution. Many of the HDAC1-binding altered promoters regulate genes involved in hematopoiesis, transcriptional regulation and signal transduction. HDAC1 binding patterns were associated with patients' event free survival. This is the first study to determine HDAC1 modification patterns in a large number of AML and ALL specimens. Our findings suggest that dyslocalization of HDAC1 is a common feature in AML. Importantly, HDAC1 modifications possess prognostic power for patient survival. Our findings suggest that altered HDAC1 localization is an explanation for the observed benefit of HDAC inhibitors in AML therapy.",

keywords = "Adolescent, Adult, Aged, Child, Child, Preschool, Chromatin, Female, Hematopoiesis, Histone Deacetylase 1, Humans, Infant, Leukemia, Myeloid, Acute, Male, Middle Aged, Prognosis, Promoter Regions, Genetic, Protein Binding, Survival Analysis, Tumor Markers, Biological, Young Adult",

author = "Lara Tickenbrock and Hans-Ulrich Klein and Cristina Trento and Antje Hascher and Stefanie G{\"o}llner and Nicole B{\"a}umer and Robert Kuss and Shuchi Agrawal and Gesine Bug and Hubert Serve and Christian Thiede and Gerhard Ehninger and Stadt, {Udo Zur} and Michael McClelland and Yipeng Wang and Anke Becker and Steffen Koschmieder and Berdel, {Wolfgang E} and Martin Dugas and Carsten M{\"u}ller-Tidow and {Study Alliance Leukemia Group}",

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doi = "10.1016/j.leukres.2010.11.006",

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T1 - Increased HDAC1 deposition at hematopoietic promoters in AML and its association with patient survival

AU - Tickenbrock, Lara

AU - Klein, Hans-Ulrich

AU - Trento, Cristina

AU - Hascher, Antje

AU - Göllner, Stefanie

AU - Bäumer, Nicole

AU - Kuss, Robert

AU - Agrawal, Shuchi

AU - Bug, Gesine

AU - Serve, Hubert

AU - Thiede, Christian

AU - Ehninger, Gerhard

AU - Stadt, Udo Zur

AU - McClelland, Michael

AU - Wang, Yipeng

AU - Becker, Anke

AU - Koschmieder, Steffen

AU - Berdel, Wolfgang E

AU - Dugas, Martin

AU - Müller-Tidow, Carsten

AU - Study Alliance Leukemia Group

PY - 2011/5/1

Y1 - 2011/5/1

N2 - Epigenetic changes play a crucial role in leukemogenesis. HDACs are frequently recruited to target gene promoters by balanced translocation derived oncogenic fusion proteins. As important epigenetic effector mechanisms, histone deacetylases (HDAC) have emerged as potential therapeutic targets. However, the patterns of HDAC1 localization and the role of HDACs in leukemia pathogenesis remain to be elucidated. Using ChIP-Chip analyses we analyzed HDAC1 deposition patterns at more than 10,000 gene promoters in a large cohort of leukemia patients and CD34+ controls. HDAC1 binding was significantly increased in AML blasts compared to CD34+ progenitor cells at 130 gene promoters whereas decreased binding was observed at 66 gene promoters. Distinct HDAC1 binding patterns occurred in AML subtypes with balanced translocations t(15;17), t(8;21) and inv(16). In addition, a more generalized signature was established, that revealed an AML specific pattern of HDAC1 distribution. Many of the HDAC1-binding altered promoters regulate genes involved in hematopoiesis, transcriptional regulation and signal transduction. HDAC1 binding patterns were associated with patients' event free survival. This is the first study to determine HDAC1 modification patterns in a large number of AML and ALL specimens. Our findings suggest that dyslocalization of HDAC1 is a common feature in AML. Importantly, HDAC1 modifications possess prognostic power for patient survival. Our findings suggest that altered HDAC1 localization is an explanation for the observed benefit of HDAC inhibitors in AML therapy.

AB - Epigenetic changes play a crucial role in leukemogenesis. HDACs are frequently recruited to target gene promoters by balanced translocation derived oncogenic fusion proteins. As important epigenetic effector mechanisms, histone deacetylases (HDAC) have emerged as potential therapeutic targets. However, the patterns of HDAC1 localization and the role of HDACs in leukemia pathogenesis remain to be elucidated. Using ChIP-Chip analyses we analyzed HDAC1 deposition patterns at more than 10,000 gene promoters in a large cohort of leukemia patients and CD34+ controls. HDAC1 binding was significantly increased in AML blasts compared to CD34+ progenitor cells at 130 gene promoters whereas decreased binding was observed at 66 gene promoters. Distinct HDAC1 binding patterns occurred in AML subtypes with balanced translocations t(15;17), t(8;21) and inv(16). In addition, a more generalized signature was established, that revealed an AML specific pattern of HDAC1 distribution. Many of the HDAC1-binding altered promoters regulate genes involved in hematopoiesis, transcriptional regulation and signal transduction. HDAC1 binding patterns were associated with patients' event free survival. This is the first study to determine HDAC1 modification patterns in a large number of AML and ALL specimens. Our findings suggest that dyslocalization of HDAC1 is a common feature in AML. Importantly, HDAC1 modifications possess prognostic power for patient survival. Our findings suggest that altered HDAC1 localization is an explanation for the observed benefit of HDAC inhibitors in AML therapy.

KW - Adolescent

KW - Adult

KW - Aged

KW - Child

KW - Child, Preschool

KW - Chromatin

KW - Female

KW - Hematopoiesis

KW - Histone Deacetylase 1

KW - Humans

KW - Infant

KW - Leukemia, Myeloid, Acute

KW - Male

KW - Middle Aged

KW - Prognosis

KW - Promoter Regions, Genetic

KW - Protein Binding

KW - Survival Analysis

KW - Tumor Markers, Biological

KW - Young Adult

U2 - 10.1016/j.leukres.2010.11.006

DO - 10.1016/j.leukres.2010.11.006

M3 - Journal article

C2 - 21176959

SN - 0145-2126

VL - 35

SP - 620

EP - 625

JO - Leukemia Research

JF - Leukemia Research

IS - 5

ER -

Increased HDAC1 deposition at hematopoietic promoters in AML and its association with patient survival

Abstract

Keywords

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