T-cell Dysfunction upon Expression of MYC with Altered Phosphorylation at Threonine 58 and Serine 62

Colin J. Daniel, Carl Pelz, Xiaoyan Wang, Michael W. Munks, Aaron Ko, Dhaarini Murugan, Sarah A. Byers, Eleonora Juarez, Karyn L. Taylor, Guang Fan, Lisa M. Coussens, Jason M. Link, Rosalie C. Sears

Research output: Contribution to journalArticlepeer-review


As a transcription factor that promotes cell growth, proliferation, and apoptosis, c-MYC (MYC) expression in the cell is tightly controlled. Disruption of oncogenic signaling pathways in human cancers can increase MYC protein stability, due to altered phosphorylation ratios at two highly conserved sites, Threonine 58 (T58) and Serine 62 (S62). The T58 to Alanine mutant (T58A) of MYC mimics the stabilized, S62 phosphorylated, and highly oncogenic form of MYC. The S62A mutant is also stabilized, lacks phosphorylation at both Serine 62 and Threonine 58, and has been shown to be nontransforming in vitro. However, several regulatory proteins are reported to associate with MYC lacking phosphorylation at S62 and T58, and the role this form of MYC plays in MYC transcriptional output and in vivo oncogenic function is understudied. We generated conditional c-Myc knock-in mice in which the expression of wild-type MYC (MYCWT), the T58A mutant (MYCT58A), or the S62A mutant (MYCS62A) with or without expression of endogenous Myc is controlled by the T-cell-specific Lck-Cre recombinase. MYCT58A expressing mice developed clonal T-cell lymphomas with 100% penetrance and conditional knock-out of endogenous Myc accelerated this lymphomagenesis. In contrast, MYCS62A mice developed clonal T-cell lymphomas at a much lower penetrance, and the loss of endogenous MYC reduced the penetrance while increasing the appearance of a non-transgene driven B-cell lymphoma with splenomegaly. Together, our study highlights the importance of regulated phosphorylation of MYC at T58 and S62 for T-cell transformation.

Original languageEnglish (US)
Pages (from-to)1151-1165
Number of pages15
JournalMolecular Cancer Research
Issue number7
StatePublished - Jul 2022

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research


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