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Leukemic fusion genes MLL/AF4 and AML1/MTG8 support leukemic self-renewal by controlling expression of the telomerase subunit TERT

MLL/AF4 and AML/MTG8 represent two leukemic fusion genes, which are most frequently found in infant acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), respectively. We examined the influence of MLL/AF4 and AML1/MTG8 fusion genes on the expression of TERT coding for the telomerase p...

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Main Authors: Gessner, Anja (Author) , Thomas, M. (Author) , Garrido Castro, P. (Author) , Büchler, L. (Author) , Scholz, A. (Author) , Brümmendorf, T. H. (Author) , Martínez Soria, Natalia (Author) , Vormoor, J. (Author) , Greil, Johann (Author) , Heidenreich, O. (Author)
Format: Article (Journal)
Language:English
Published: 5 August 2010
In: Leukemia
Year: 2010, Volume: 24, Issue: 10, Pages: 1751-1759
ISSN:1476-5551
DOI:10.1038/leu.2010.155
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/leu.2010.155
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/leu2010155
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Author Notes:A. Gessner, M. Thomas, P. Garrido Castro, L. Büchler, A. Scholz, T. H. Brümmendorf, N. Martinez Soria, J. Vormoor, J. Greil and O. Heidenreich
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Summary:MLL/AF4 and AML/MTG8 represent two leukemic fusion genes, which are most frequently found in infant acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), respectively. We examined the influence of MLL/AF4 and AML1/MTG8 fusion genes on the expression of TERT coding for the telomerase protein subunit, and subsequently telomerase activity in t(4;11)-positive ALL and t(8;21)-positive cell lines, respectively. MLL/AF4 suppression diminished telomerase activity and expression of TERT. Blocking pro-apoptotic caspase activation in conjunction with MLL/AF4 knockdown enhanced the inhibition of TERT gene expression, which suggests that MLL/AF4 depletion does not reduce TERT expression levels by inducing apoptosis. Knockdown of HOXA7, a direct transcriptional target of MLL/AF4 fusion gene, caused a reduction of telomerase and TERT to an extent similar to that observed with MLL/AF4 suppression. Chromatin immunoprecipitation of SEM cells, using ectopically expressed FLAG-tagged Hoxa7, indicates HOXA7 binding site in the TERT promoter region. Furthermore, suppression of the AML1/MTG8 fusion gene was associated with severely reduced clonogenicity, induction of replicative senescence, impaired TERT expression and accelerated telomere shortening. We thus present findings that show a mechanistic link between leukemic fusion proteins, essential for development and maintenance of leukemia, and telomerase, a key element of both normal and malignant self-renewal.
Item Description:Gesehen am 03.03.2023
Physical Description:Online Resource
ISSN:1476-5551
DOI:10.1038/leu.2010.155

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