title: A common functional consequence of tumor-derived mutations within c-MYC.
abstract: 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.
authors.affiliation: 1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA [2] Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Chakraborty
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Scuoppo
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Dey
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: L R
authors.initials: LR
authors.lastname: Thomas
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Lorey
authors.affiliation: 1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA [2] Howard Hughes Medical Institute, New York, NY, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Lowe
authors.affiliation: 1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA [2] Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: W P
authors.identifier: 0000000239000978
authors.initials: WP
authors.lastname: Tansey
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D004247:DNA / Q000032:analysis; D006801:Humans; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism*
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D004247:DNA