DNA methylation-independent loss of RARA gene expression in acute myeloid leukemia
Open accessAbstract
The retinoic acid receptor (RAR) α gene (RARA) encodes 2 major isoforms and mediates positive effects of all-trans retinoic acid (ATRA) on myelomonocytic differentiation. Expression of the ATRA-inducible (RARα2) isoform increases with myelomonocytic differentiation and appears to be down-regulated in many acute myeloid leukemia (AML) cell lines. Here, we demonstrate that relative to normal myeloid stem/progenitor cells, RARα2 expression is dramatically reduced in primary AML blasts. Expression of the RARα1 isoform is also significantly reduced in primary AML cells, but not in AML cell lines. Although the promoters directing expression of RARα1 and RARα2 are respectively unmethylated and methylated in AML cell lines, these regulatory regions are unmethylated in all the AML patient cell samples analyzed. Moreover, in primary AML cells, histones associated with the RARα2 promoter possessed diminished levels of H3 acetylation and lysine 4 methylation. These results underscore the complexities of the mechanisms responsible for deregulation of gene expression in AML and support the notion that diminished RARA expression contributes to leukemogenesis.
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Both RARA1 and RARA2 promoters are unmethylated in AML patient samples, while histones associated with the RARA2 promoter have decreased levels of overall acetylation of histone H3 and decreased levels of di-methylation of histone H3 lysine 4.
“Moreover, both RARA1 and RARA2 promoters (Glasow et al, 2008) are unmethylated in AML patient samples, while histones associated with the RARA2 promoter have decreased levels of overall acetylation of histone H3 and decreased levels of di-methylation of histone H3 lysine 4.”
From Unlocking the potential of retinoic acid in anticancer therapy (2014) · cites this paper as Glasow et al, 2008
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Self-citation
- Authors
- Glasow, A., Barrett, A., Petrie, K., Gupta, R., Boix-Chornet, M., Zhou, D.-C., Grimwade, D., Gallagher, R., von Lindern, M., Waxman, S., Enver, T., Hildebrandt, G., & Zelent, A.
- Affiliations
- Institute of Cancer Research (GB)
- John Radcliffe Hospital (GB)
- Albert Einstein College of Medicine (US)
- King's College London (GB)
- Department of Hematology, Erasmus Medical Centre, Rotterdam, the Netherlands; and
- Icahn School of Medicine at Mount Sinai (US)
- Leipzig University (DE)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2008-02-15
- Volume
- 111
- Issue
- 4
- Pages
- 2374-2377
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2016087553
- Cited by
- 44
- References
- 31
- Citations by year
- 2025: 1 · 2023: 3 · 2022: 1 · 2021: 3 · 2020: 2 · 2019: 4 · 2018: 3 · 2017: 4 · 2016: 1 · 2015: 1 · 2014: 6 · 2013: 1 · 2012: 5
- FWCI
- 0.66
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Sunderland Repository (University of Sunderland) (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- retinoic acid receptor alpha, acute myeloid leukemia, DNA methylation, histone acetylation, promoter regulation, gene expression dysregulation, leukemogenesis, myelomonocytic differentiation, all-trans retinoic acid
- MeSH terms
- Retinoic Acid Receptor alpha, Bone Marrow Cells, Cell Differentiation, Humans, Promoter Regions, Genetic, Tretinoin, Leukemia, Myeloid, Acute, Gene Expression Regulation, Neoplastic, Receptors, Retinoic Acid, DNA Methylation
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