Journal
NEOPLASIA
Volume 16, Issue 1, Pages 21-U48Publisher
ELSEVIER SCIENCE INC
DOI: 10.1593/neo.131658
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Funding
- Ligue Nationale Contre le Cancer (Comites de l'Ain et du Rhone)
- Fondation de France
- Association Laurette Fugain
- Association pour la Recherche sur le Cancer (ARC)
- Association Guillaume Espoir
- Agence Nationale pour la Recherche
- AMGEN
- Celgene
- Novartis
- Centre Leon Berard
- Hospices Civils de Lyon
- University Lyon I
- Centre National pour la Recherche Scientifique
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Societe Francaise d'Hematologie
- ARC
- Guillaume Espoir Association
- INSERM
- Hospices Civils de Lyon (AVIE-SAN CHRT program)
- Lyon I University
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Although numerous factors have been found to modulate hTERT transcription, the mechanism of its repression in certain leukemias remains unknown. We show here that DEK represses hTERT transcription through its enrichment on the hTERT promoter in cells from chronic and acute myeloid leukemias, chronic lymphocytic leukemia, but not acute lymphocytic leukemias where hTERT is overexpressed. We isolated DEK from the hTERT promoter incubated with nuclear extracts derived from fresh acute myelogenous leukemia (AML) cells and from cells expressing Tax, an hTERT repressor encoded by the human T cell leukemia virus type 1. In addition to the recruitment of DEK, the displacement of two potent known hTERT transactivators from the hTERT promoter characterized both AML cells and Tax-expressing cells. Reporter and chromatin immunoprecipitation assays permitted to map the region that supports the repressive effect of DEK on hTERT transcription, which was proportionate to the level of DEK-promoter association but not with the level of DEK expression. Besides hTERT repression, this context of chromatin redistribution of DEK was found to govern about 40% of overall transcriptional modifications, including those of cancer-prone genes. In conclusion, DEK emerges as an hTERT repressor shared by various leukemia subtypes and seems involved in the deregulation of numerous genes associated with leukemogenesis.
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