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Increased HDAC1 deposition at hematopoietic promoters in AML and its association with patient survival.
- Source :
-
Leukemia research [Leuk Res] 2011 May; Vol. 35 (5), pp. 620-5. Date of Electronic Publication: 2010 Dec 22. - Publication Year :
- 2011
-
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.<br /> (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Subjects :
- Adolescent
Adult
Aged
Biomarkers, Tumor metabolism
Child
Child, Preschool
Chromatin metabolism
Female
Humans
Infant
Leukemia, Myeloid, Acute diagnosis
Leukemia, Myeloid, Acute genetics
Male
Middle Aged
Prognosis
Protein Binding physiology
Survival Analysis
Young Adult
Hematopoiesis genetics
Histone Deacetylase 1 metabolism
Leukemia, Myeloid, Acute metabolism
Leukemia, Myeloid, Acute mortality
Promoter Regions, Genetic physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1873-5835
- Volume :
- 35
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Leukemia research
- Publication Type :
- Academic Journal
- Accession number :
- 21176959
- Full Text :
- https://doi.org/10.1016/j.leukres.2010.11.006