A tumorigenesis threshold for endogenous Myc revealed by dosage-compensation for Myc haploinsufficiency in the absence of p53.

The proto-oncogene is crucial for neoplasia in most tumors. Overexpressed, oncogenic MYC amplifies the flux through most major processes but does not specify a unique carcinogenic pathway. This "amplifier" model suggests that MYC must exceed an expression threshold to become oncogenic. We designed a genetic test of this model, using the mouse null mutant ( ) as a highly robust tumor generator to examine the effect of a modest change in the endogenous Myc level ( ). Strikingly, tumor-free survival is greatly extended in p53KO mice with haploid gene-dosage, yet in the tumors that do develop (mainly hemangiosarcomas and thymic lymphomas), their Myc deficit has been invariably compensated either by increasing genomic dosage (hemangiosarcomas) or expression (lymphomas). Furthermore, acutely halving the endogenous gene-dosage in established tumor allografts curtails growth rates. These results indicate that even an incremental reduction of MYC activity can be salutary in cancer and that one of the major tumor suppressor functions of p53 derives from its ability to prevent overexpression. Myc generates acute DNA damage by several mechanisms and accordingly, p53's anti-Myc function may be inextricably linked to its role in genome integrity surveillance.