ePrints

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

Lookup NU author(s): Dr Andreas Gessner, Patricia Garrido Castro, Dr Anja Scholz, Professor Hermann Josef Vormoor, Professor Olaf Heidenreich

Downloads

• Accepted version [.pdf]

Abstract

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.

Publication metadata

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

Altmetrics

Funding

Share