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Lookup NU author(s): Dr Andreas Gessner, Patricia Garrido Castro, Dr Anja Scholz, Professor Josef Vormoor, Professor Olaf Heidenreich
This is the authors' accepted manuscript of an article that has been published in its final definitive form by Nature Publishing Group, 2010.
For re-use rights please refer to the publisher's terms and conditions.
LL/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.
Author(s): Gessner A, Thomas M, Garrido Castro P, Büchler L, Scholz A, Brümmendorf TH, Martinez Soria N, Vormoor J, Greil J, Heidenreich O
Publication type: Article
Publication status: Published
Journal: Leukemia
Year: 2010
Volume: 24
Issue: 10
Pages: 1751-1759
Print publication date: 05/08/2010
Date deposited: 10/11/2010
ISSN (print): 0887-6924
ISSN (electronic): 1476-5551
Publisher: Nature Publishing Group
URL: http://dx.doi.org/10.1038/leu.2010.155
DOI: 10.1038/leu.2010.155
PubMed id: 20686504
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