2. Academic Validation
  3. Tuberous sclerosis complex is required for tumor maintenance in MYC-driven Burkitt's lymphoma

Tuberous sclerosis complex is required for tumor maintenance in MYC-driven Burkitt's lymphoma

  • EMBO J. 2018 Nov 2;37(21):e98589. doi: 10.15252/embj.201798589.
Götz Hartleben 1 2,  Christine Müller 1 2,  Andreas Krämer 2,  Heiko Schimmel 3,  Laura M Zidek 2,  Carsten Dornblut 2,  René Winkler 4,  Sabrina Eichwald 2,  Gertrud Kortman 1,  Christian Kosan 4,  Joost Kluiver 5,  Iver Petersen 3,  Anke van den Berg 5,  Zhao-Qi Wang 2,  Cornelis F Calkhoven 6 2
Affiliations

Affiliations

  • 1 European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
  • 2 Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
  • 3 Institute for Pathology, Jena University Hospital, Jena, Germany.
  • 4 Center for Molecular Biomedicine, Friedrich Schiller University, Jena, Germany.
  • 5 Department of Pathology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
  • 6 European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands c.f.calkhoven@umcg.nl.
PMID: 30237309 DOI: 10.15252/embj.201798589
Abstract

The tuberous sclerosis complex (TSC) 1/2 is a negative regulator of the nutrient-sensing kinase mechanistic target of rapamycin complex (mTORC1), and its function is generally associated with tumor suppression. Nevertheless, biallelic loss of function of TSC1 or TSC2 is rarely found in malignant tumors. Here, we show that TSC1/2 is highly expressed in Burkitt's lymphoma cell lines and patient samples of human Burkitt's lymphoma, a prototypical MYC-driven Cancer. Mechanistically, we show that MYC induces TSC1 expression by transcriptional activation of the TSC1 promoter and repression of miR-15a. TSC1 knockdown results in elevated mTORC1-dependent mitochondrial respiration enhanced ROS production and Apoptosis. Moreover, TSC1 deficiency attenuates tumor growth in a xenograft mouse model. Our study reveals a novel role for TSC1 in securing homeostasis between MYC and mTORC1 that is required for cell survival and tumor maintenance in Burkitt's lymphoma. The study identifies TSC1/2 inhibition and/or mTORC1 hyperactivation as a novel therapeutic strategy for MYC-driven cancers.

Keywords

MYC; Burkitt's lymphoma; TSC1/2; cancer; mTORC1.

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