Lymphomas that recur after MYC suppression continue to exhibit oncogene addiction

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-10, Vol.108 (42), p.17432-17437
• Main Authors: Choi, Peter S., van Riggelen, Jan, Gentles, Andrew J., Bachireddy, Pavan, Rakhra, Kavya, Adam, Stacey J., Plevritis, Sylvia K., Felsher, Dean W.
• Format: Article
• Language: English
• Subjects: Acute lymphatic leukemia; Acute T cell leukemia; Addiction; Animal models; Animals; Apoptosis; Biological Sciences; Cancer; Differentiation; Doxycycline; Gene Expression; Gene Knockdown Techniques; gene overexpression; Genes, myc; Genetic mutation; Genomics; Humans; loci; Lymphocytes T; lymphocytic leukemia; Lymphoma; Lymphoma, T-Cell - genetics; Lymphoma, T-Cell - therapy; Mice; Mice, Transgenic; Mutation; Myc protein; Neoplasm Recurrence, Local - genetics; Oncogenes; Phenotype; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - therapy; remission; RNA, Small Interfering - genetics; Rodents; Senescence; T cell receptors; tetracycline; Tetracycline Resistance - genetics; Tetracyclines; Trans-Activators - genetics; transcriptome; Transgenes; Transgenic animals; Transgenic mice; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1107303108

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.