Stabilization of c-Myc protein by CAMKII? promotes T-cell lymphoma

Although high c-Myc protein expression is observed alongside c-Myc gene amplification in some cancers, in most cases protein overexpression occurs while the amplified gene is largely absent, e.g. T-cell lymphoma (TCL). Here, Ca2+/calmodulin-dependent protein kinase II ? (CAMKII?) was shown to stabilize c-Myc protein by directly phosphorylating at serine 62 (S62), which represents a hitherto unknown mechanism of c-Myc protein overexpression. Further, CAMKII? was shown to be essential for tumor maintenance. Inhibiting CAMKII? with a potent CAMKII?-specific inhibitor destabilized c-Myc and reduced tumor burden dramatically. Importantly, high CAMKII? in clinical patient specimens positively correlated with increased c-Myc / pS62-c-Myc expression. Together, the CAMKII?:c-Myc axis critically influences the development and maintenance of TCL, and represent a novel therapeutic target for TCL. Overall design: We investigated how deleting CAMKII? suppressed the development of MNU-induced TCL in mice. Through RNA-sequencing, we analyzed the gene expression profiles of the thymuses of both wild-type and CAMKII?-/- mice, under either malignant (with MNU) or normal (without MNU) conditions.