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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| Hauptverfasser: | , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
5 August 2010
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| In: |
Leukemia
Year: 2010, Jahrgang: 24, Heft: 10, Pages: 1751-1759 |
| ISSN: | 1476-5551 |
| DOI: | 10.1038/leu.2010.155 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/leu.2010.155 Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/leu2010155 
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| Verfasserangaben: | 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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| 245 | 1 | 0 | |a Leukemic fusion genes MLL/AF4 and AML1/MTG8 support leukemic self-renewal by controlling expression of the telomerase subunit TERT |c 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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| 520 | |a 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. | ||
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