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.
authors.affiliation: Department of Medicine A, Hematology and Oncology, University of Münster, Münster, Germany.
authors.forename: Lara
authors.initials: L
authors.lastname: Tickenbrock
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Klein
authors.forename: Cristina
authors.initials: C
authors.lastname: Trento
authors.forename: Antje
authors.initials: A
authors.lastname: Hascher
authors.forename: Stefanie
authors.initials: S
authors.lastname: Göllner
authors.forename: Nicole
authors.initials: N
authors.lastname: Bäumer
authors.forename: Robert
authors.initials: R
authors.lastname: Kuss
authors.forename: Shuchi
authors.initials: S
authors.lastname: Agrawal
authors.forename: Gesine
authors.initials: G
authors.lastname: Bug
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
authors.forename: Christian
authors.initials: C
authors.lastname: Thiede
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
authors.forename: Udo Zur
authors.initials: UZ
authors.lastname: Stadt
authors.forename: Michael
authors.initials: M
authors.lastname: McClelland
authors.forename: Yipeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Anke
authors.initials: A
authors.lastname: Becker
authors.forename: Steffen
authors.initials: S
authors.lastname: Koschmieder
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.forename: Martin
authors.initials: M
authors.lastname: Dugas
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002843:Chromatin / Q000378:metabolism; D005260:Female; D006410:Hematopoiesis / Q000235:genetics*; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D002843:Chromatin; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1