CAMKIIγ Stabilizes MYC to Promote T-cell Lymphomagenesis

Dysregulation of MYC occurs in many cancers including T-cell lymphoma, where MYC is generally overexpressed without gene amplification. However, the mechanism by which MYC is overexpressed in T-cell lymphoma has yet to be determined. The multifunctional serine/threonine kinase Ca²⁺/calmodulin-dependent protein kinase II γ (CAMKIIγ; encoded by CAMK2G) has been linked to cancer and CAMK2G is synthetically lethal with MYC overexpression, prompting Gu and colleagues to investigate the role of CAMKIIγ in T-cell lymphoma. Deletion of Camk2g suppressed the formation of carcinogen-induced lymphoma in mice, and MYC target genes were downregulated in Camk2g^−/− cells. CAMKIIγ depletion resulted in a decrease in MYC protein levels, but not MYC mRNA levels, suggesting an effect on MYC protein stability. Mechanistically, CAMKIIγ stabilized MYC by directly phosphorylating it at Ser62, thereby promoting cellular proliferation and lymphomagenesis. Pharmacologic inhibition of CAMKIIγ with the specific inhibitor BBM suppressed the growth of T-cell lymphoma cells in vitro. Further, BBM reduced MYC protein levels, suppressed T-cell lymphomagenesis, and reduced tumor burden in vivo, suggesting that CAMKIIγ may be an effective therapeutic target in T-cell lymphoma. In tumors from 32 patients with T-cell lymphoma, CAMKIIγ was highly expressed compared with benign lymph nodes, and CAMKIIγ expression was positively associated with increased protein expression and phosphorylation of MYC. In addition to demonstrating that CAMKIIγ promotes MYC stability in T-cell lymphoma, these findings suggest that inhibition of CAMKIIγ may represent a potential therapeutic strategy to indirectly target MYC to suppress lymphomagenesis.

Gu Y, Zhang J, Ma X, Kim BW, Wang H, Li J, et al. Stabilization of the c-MYC protein by CAMKIIγ promotes T cell lymphoma. Cancer Cell 2017;32:115–28.e7.