Stabilization of the c-Myc Protein by CAMKIIγ Promotes T Cell Lymphoma

Although high c-Myc protein expression is observed alongside MYC amplification in some cancers, in most cases protein overexpression occurs in the absence of gene amplification, e.g., T cell lymphoma (TCL). Here, Ca2+/calmodulin-dependent protein kinase II γ (CAMKIIγ) was shown to stabilize the c-Myc protein by directly phosphorylating it at serine 62 (S62). Furthermore, CAMKIIγ was shown to be essential for tumor maintenance. Inhibition of CAMKIIγ with a specific inhibitor destabilized c-Myc and reduced tumor burden. Importantly, high CAMKIIγ levels in patient TCL specimens correlate with increased c-Myc and pS62-c-Myc levels. Together, the CAMKIIγ:c-Myc axis critically influences the development and maintenance of TCL and represents a potential therapeutic target for TCL. [Display omitted] •CAMKIIγ:c-Myc axis is essential for T cell lymphomagenesis•CAMKIIγ stabilizes the c-Myc protein by direct phosphorylation it at S62 in TCL•Targeting CAMKIIγ destabilizes the c-Myc protein and reduces tumor burden•C-Myc and CAMKIIγ overexpress in human TCL with a positive correlation T cell lymphomas (TCL) overexpress the c-Myc protein without MYC rearrangements or amplification. Gu et al. show that CAMKIIγ stabilizes c-Myc by phosphorylating it at Ser62, that the CAMKIIγ level positively correlates with the c-Myc level in patient TCL, and that inhibition of CAMKIIγ reduces TCL burden in mice.