The Identification of (ETV6)/RUNX1-Regulated Genes in Lymphopoiesis Using Histone Deacetylase Inhibitors in ETV6/RUNX1-Positive Lymphoid Leukemic Cells
Abstract
Purpose Chimeric transcription factor ETV6/RUNX1 (TEL/AML1) is believed to cause pathologic block in lymphoid cell development via interaction with corepressor complex and histone deacetylase. We wanted to show the regulatory effect of ETV6/RUNX1 and its reversibility by histone deacetylase inhibitors (HDACi), as well as to identify potential ETV6/RUNX1-regulated genes. Experimental design We used luciferase assay to show the interaction of ETV6/RUNX1 protein, ETV6/RUNX1-regulated gene, and HDACi. To identify ETV6/RUNX1-regulated genes, we used expression profiling and HDACi in lymphoid cells. Next, using the flow cytometry and quantitative reverse transcription-PCR, we measured differentiation changes in gene and protein expression after HDACi treatment. Results Luciferase assay showed repression of granzyme B expression by ETV6/RUNX1 protein and the reversibility of this effect by HDACi. Proving this regulatory role of ETV6/RUNX1, we identified, using complex statistical analysis, 25 genes that are potentially regulated by ETV6/RUNX1 protein. In four selected genes with known role in the cell cycle regulation (JunD, ACK1, PDGFRB, and TCF4), we confirmed expression changes after HDACi by quantitative analysis. After HDACi treatment, ETV6/RUNX1-positive cells showed immunophenotype changes resembling differentiation process compared with other leukemic cells (BCR/ABL, ETV6/PDGFRB positive). Moreover, ETV6/RUNX1-positive leukemic cells accumulated in G(1)-G(0) phase after HDAC…
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The study provided a core network of epigenetically inactivated genes commonly inhibited by the transcriptional repressor ETV6-RUNX1 fusion oncogene.
“Our study provided a core network of epigenetically inactivated genes commonly inhibited by the transcriptional repressor ETV6–RUNX1 fusion oncogene (57)”
From PU.1-Dependent Enhancer Inhibition Separates <i>Tet2</i> -Deficient Hematopoiesis from Malignant Transformation (2022) · cites this paper as [57]
Cites
Both TEL and AML-1 Contribute Repression Domains to the t(12;21) Fusion Protein
Fenrick, R., Amann, J. M., Lutterbach, B., Wang, L., Westendorf, J. J., Downing, J. R., & Hiebert, S. W. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.10.6566 · Cited by 162 · see citing works
Chakrabarti, S. R., & Nucifora, G. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.1605 · Cited by 149 · see citing works
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Aivalioti, M. M., Bartholdy, B. A., Pradhan, K., Bhagat, T. D., Zintiridou, A., Jeong, J. J., Thiruthuvanathan, V. J., Pujato, M., Paranjpe, A., Zhang, C., et al. (2022) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-21-0226 · Cited by 22 · see citing works
“Our study provided a core network of epigenetically inactivated genes commonly inhibited by the transcriptional repressor ETV6–RUNX1 fusion oncogene (57), which suggests a role for RUNX1 in the activation of these loci, consistent with the known function of PU.”
Result
- Authors
- Starkova, J., Madzo, J., Cario, G., Kalina, T., Ford, A., Zaliova, M., Hrusak, O., & Trka, J.
- Affiliations
- 1Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology/Oncology, 2nd Medical School, Charles University Prague, Prague, Czech Republic;
- University Hospital Schleswig-Holstein (DE)
- Institute of Cancer Research (GB)
- Charles University (CZ)
- Venue
- Clinical Cancer Research
- Published
- 2007-03-15
- Volume
- 13
- Issue
- 6
- Pages
- 1726-1735
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2013480914
- Cited by
- 24
- References
- 2
- Citations by year
- 2025: 1 · 2023: 2 · 2022: 4 · 2017: 3 · 2016: 2 · 2015: 2 · 2013: 1 · 2012: 3
- FWCI
- 1.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- ETV6-RUNX1, TEL-AML1, histone deacetylase inhibitors, lymphoid leukemia, lymphocyte development, granzyme B, gene expression regulation, corepressor complex, cell cycle arrest, G1 phase, JunD, ACK1, PDGFRβ, TCF4, transcriptional repression
- MeSH terms
- ETS Translocation Variant 6 Protein, Humans, Leukemia, Lymphoid, Repressor Proteins, Tumor Cells, Cultured, Gene Expression Regulation, Leukemic, Apoptosis, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Lymphopoiesis, Cell Proliferation, Core Binding Factor Alpha 2 Subunit, Proto-Oncogene Proteins c-ets, Granzymes, Histone Deacetylase Inhibitors
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