The identification of (ETV6)/RUNX1-regulated genes in lymphopoiesis using histone deacetylase inhibitors in ETV6/RUNX1-positive lymphoid leukemic cells
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
17325341
DOI
10.1158/1078-0432.ccr-06-2569
PII: 1078-0432.CCR-06-2569
Knihovny.cz E-zdroje
- MeSH
- apoptóza účinky léků MeSH
- granzymy genetika MeSH
- inhibitory histondeacetylas * MeSH
- lidé MeSH
- lymfoidní leukemie genetika patologie MeSH
- lymfopoéza účinky léků genetika MeSH
- nádorové buňky kultivované MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- proliferace buněk účinky léků MeSH
- protein ETS, translokační varianta 6 MeSH
- protein PEBP2A2 genetika fyziologie MeSH
- protoonkogenní proteiny c-ets genetika fyziologie MeSH
- regulace genové exprese u leukemie * účinky léků MeSH
- represorové proteiny genetika fyziologie MeSH
- stanovení celkové genové exprese MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- granzymy MeSH
- inhibitory histondeacetylas * MeSH
- protein PEBP2A2 MeSH
- protoonkogenní proteiny c-ets MeSH
- represorové proteiny MeSH
- RUNX1 protein, human MeSH Prohlížeč
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 HDACi whereas other B-lineage leukemic cell lines showed rather unspecific changes including induction of apoptosis and decreased proliferation. CONCLUSIONS: Presented data support the hypothesis that HDACi affect ETV6/RUNX1-positive cells via direct interaction with ETV6/RUNX1 protein and that treatment with HDACi may release aberrant transcription activity caused by ETV6/RUNX1 chimeric transcription factor.
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