Activation of CaMKII? potentiates T-cell acute lymphoblastic leukemia leukemogenesis via phosphorylating FOXO3a.

ABSTRACT: Ca2+/calmodulin-dependent protein kinase II ? (CaMKII?) can regulate the proliferation and differentiation of myeloid leukemia cells and accelerate chronic myeloid leukemia blast crisis, but the role of CaMKII? in T-cell acute lymphoblastic leukemia (T-ALL) leukemogenesis remains poorly understood. We observed that activated (autophosphorylated) CaMKII? was invariably present in T-ALL cell lines and in the majority of primary T-ALL samples. Overexpression of CaMKII? enhanced the proliferation, colony formation, in vivo tumorigenesis and increased DNA damage of T-ALL leukemia cells. Furthermore, inhibition of CaMKII? activity with a pharmacologic inhibitor, gene knock-out, dominant-negative constructs or enhancement of CaMKII? activity by overexpression constructs revealed that the activated CaMKII? could phosphorylate FOXO3a. In Jurkat cells, the activated CaMKII? phosphorylated FOXO3a via directly or indirectly phosphorylating AKT, excluded FOXO3a from the nucleus and inhibited its transcriptional activity. These results indicate that the activated CaMKII? may play a key role in T-ALL leukemogenesis, and targeting CaMKII? might be a value approach in the treatment of T-ALL.

SUBMITTER: Jiang X 

PROVIDER: S-EPMC5650399 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature