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.