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Oncogenes, Fusion Genes and Tumor Suppressor Genes

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

Leukemia volume 24, pages 1751–1759 (2010)Cite this article

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Abstract

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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Acknowledgements

This work was supported by grants from the Deutsche Jose Carreras Leukämie-Stiftung (DJCLS R 07/31f to JG and OH), the Northern England Children's Cancer Research Fund (to OH and JV), Leukaemia and Lymphoma Research (08011 to OH and JV) and the Kay Kendal Leukaemia Fund (KKL329 to OH and JV). AG, MT and PGC designed and performed research and analyzed data; LB, NMS, AS and TB performed research and analyzed data; JV and JG designed research and OH designed research, analyzed data and wrote the paper.

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Author notes

  1. M Thomas

    Present address: 6Current address: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.,

  2. N Martinez Soria

    Present address: 7Current address: Departamento de Biotecnología Microbiana, Centro Nacional de Biotecnología, Madrid, Spain.,

  3. A Gessner and M Thomas: These authors contributed equally to this work.

Authors and Affiliations

  1. Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK

    A Gessner, P Garrido Castro, L Büchler, A Scholz, J Vormoor & O Heidenreich

  2. Department of Molecular Biology, Interfaculty Institute for Cell Biology, Eberhard Karls University Tübingen, Tübingen, Germany

    M Thomas & N Martinez Soria

  3. Department of Hematology and Oncology, University Medical Center II, Tübingen, Germany

    T H Brümmendorf

  4. Department of Hematology and Oncology, University Hospital Aachen, Aachen, Germany

    T H Brümmendorf

  5. Department of Hematology, Oncology, Immunology and Pneumology, Children's Hospital, Heidelberg, Germany

    J Greil

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Gessner, A., Thomas, M., Garrido Castro, P. et al. Leukemic fusion genes MLL/AF4 and AML1/MTG8 support leukemic self-renewal by controlling expression of the telomerase subunit TERT. Leukemia 24, 1751–1759 (2010). https://doi.org/10.1038/leu.2010.155

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