A common functional consequence of tumor-derived mutations within c-MYC.

Chakraborty AA, Scuoppo C, Dey S, Thomas LR, Lorey SL, Lowe SW, Tansey WP
Oncogene. 2015 34 (18): 2406-9

PMID: 24998853 · PMCID: PMC4286529 · DOI:10.1038/onc.2014.186

The relevance of changes to the coding sequence of the c-MYC oncogene to malignancy is controversial. Overexpression of a pristine form of MYC is observed in many cancers and is sufficient to drive tumorigenesis in most contexts. Yet missense changes to MYC are found in ~50% of Burkitt's lymphomas, aggregate within an amino-terminal degron important for proteasomal destruction of MYC, and where examined profoundly enhance the tumorigenic properties of MYC in vitro and in vivo. Much of the controversy surrounding these mutants stems from the limited number of mutations that have been evaluated and their clustering within a single region of the MYC protein; the highly-conserved Myc box I (MbI) element. Here, by analysis of extant genomic data sets, we identify a previously unrecognized hotspot for tumor-associated MYC mutations, located in a conserved central portion of the protein. We show that, despite their distal location in MYC, mutations in this region precisely phenocopy those in MbI in terms of stability, in vitro transformation, growth-promoting properties, in vivo tumorigenesis and ability to escape p53-dependent tumor surveillance mechanisms. The striking parallels between the behavior of tumor-derived mutations in disparate regions of the MYC protein reveals that a common molecular process is disrupted by these mutations, implying an active role for these mutations in tumorigenesis and suggesting that different therapeutic strategies may be needed for treatment of lymphomas expressing wild type versus mutant forms of MYC protein.

MeSH Terms (11)

Amino Acid Sequence Animals Cell Line, Tumor Conserved Sequence DNA Humans Lymphoma Mice Mutation, Missense NIH 3T3 Cells Proto-Oncogene Proteins c-myc

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