Lymphomas that recur after MYC suppression continue to exhibit oncogene addiction

Peter S. Choi, Jan Van Riggelen, Andrew J. Gentles, Pavan Bachireddy, Kavya Rakhra, Stacey J. Adam, Sylvia K. Plevritis, Dean W. Felsher

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

The suppression of oncogenic levels of MYC is sufficient to induce sustained tumor regression associated with proliferative arrest, differentiation, cellular senescence, and/or apoptosis, a phenomenon known as oncogene addiction. However, after prolonged inactivation of MYC in a conditional transgenic mouse model of Eμ-tTA/tetO-MYC T-cell acute lymphoblastic leukemia, some of the tumors recur, recapitulating what is frequently observed in human tumors in response to targeted therapies. Here we report that these recurring lymphomas express either transgenic or endogenous Myc, albeit in many cases at levels below those in the original tumor, suggesting that tumors continue to be addicted to MYC. Many of the recurring lymphomas (76%) harbored mutations in the tetracycline transactivator, resulting in expression of the MYC transgene even in the presence of doxycycline. Some of the remaining recurring tumors expressed high levels of endogenous Myc, which was associated with a genomic rearrangement of the endogenous Myc locus or activation of Notch1. By gene expression profiling, we confirmed that the primary and recurring tumors have highly similar transcriptomes. Importantly, shRNA-mediated suppression of the high levels of MYC in recurring tumors elicited both suppression of proliferation and increased apoptosis, confirming that these tumors remain oncogene addicted. These results suggest that tumors induced by MYC remain addicted to overexpression of this oncogene.

Original languageEnglish (US)
Pages (from-to)17432-17437
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number42
DOIs
StatePublished - Oct 18 2011

Keywords

  • T-cell acute lymphoblastic leukemia
  • Therapeutic resistance
  • Tumor recurrence

ASJC Scopus subject areas

  • General

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    Choi, P. S., Van Riggelen, J., Gentles, A. J., Bachireddy, P., Rakhra, K., Adam, S. J., Plevritis, S. K., & Felsher, D. W. (2011). Lymphomas that recur after MYC suppression continue to exhibit oncogene addiction. Proceedings of the National Academy of Sciences of the United States of America, 108(42), 17432-17437. https://doi.org/10.1073/pnas.1107303108