Publication

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

Hartleben, G., Müller, C., Krämer, A., Schimmel, H., Zidek, L. M., Dornblut, C., Winkler, R., Eichwald, S., Kortman, G., Kosan, C., Kluiver, J., Petersen, I., van den Berg, A., Wang, Z-Q. & Calkhoven, C. F., 2-Nov-2018, In : The EMBO Journal. 37, 21, 14 p., 98589.

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Article number98589
Number of pages14
JournalThe EMBO Journal
Volume37
Issue number21
Early online date20-Sep-2018
Publication statusPublished - 2-Nov-2018

    Keywords

  • Burkitt's lymphoma, cancer, mTORC1, MYC, TSC1/2, MTORC1 INHIBITOR EVEROLIMUS, C-MYC, MITOCHONDRIAL BIOGENESIS, TRANSLATION INITIATION, PROTEIN-KINASE, STEM-CELLS, CANCER, TUMORIGENESIS, ACTIVATION, GENE

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