Jiang Xudong, Wu Zhaoxing, Lu Xiaoya, Zhang Xuzhao, Yu Qingfeng, Gan Yichao, Wu Bowen, Xu Ying, Zheng Weiwei, Zhang Lei, Xu Fei, Ma An, Gan Xiaoxian, Huang Silvia, Yu Xiaofang, Huang Wendong, Xu Rongzhen
Department of Hematology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China.
Cancer Institute of Zhejiang University, Hangzhou, 310009 China.
Oncotarget. 2017 Aug 24;8(43):75050-75064. doi: 10.18632/oncotarget.20504. eCollection 2017 Sep 26.
Ca/calmodulin-dependent protein kinase II γ (CaMKIIγ) can regulate the proliferation and differentiation of myeloid leukemia cells and accelerate chronic myeloid leukemia blast crisis, but the role of CaMKIIγ in T-cell acute lymphoblastic leukemia (T-ALL) leukemogenesis remains poorly understood. We observed that activated (autophosphorylated) CaMKIIγ was invariably present in T-ALL cell lines and in the majority of primary T-ALL samples. Overexpression of CaMKIIγ enhanced the proliferation, colony formation, tumorigenesis and increased DNA damage of T-ALL leukemia cells. Furthermore, inhibition of CaMKIIγ activity with a pharmacologic inhibitor, gene knock-out, dominant-negative constructs or enhancement of CaMKIIγ activity by overexpression constructs revealed that the activated CaMKIIγ could phosphorylate FOXO3a. In Jurkat cells, the activated CaMKIIγ phosphorylated FOXO3a via directly or indirectly phosphorylating AKT, excluded FOXO3a from the nucleus and inhibited its transcriptional activity. These results indicate that the activated CaMKIIγ may play a key role in T-ALL leukemogenesis, and targeting CaMKIIγ might be a value approach in the treatment of T-ALL.
钙/钙调蛋白依赖性蛋白激酶IIγ（CaMKIIγ）可调节髓系白血病细胞的增殖和分化，并加速慢性髓系白血病急变期，但CaMKIIγ在T细胞急性淋巴细胞白血病（T-ALL）白血病发生中的作用仍知之甚少。我们观察到，活化的（自磷酸化的）CaMKIIγ始终存在于T-ALL细胞系和大多数原发性T-ALL样本中。CaMKIIγ的过表达增强了T-ALL白血病细胞的增殖、集落形成、肿瘤发生并增加了DNA损伤。此外，用药物抑制剂抑制CaMKIIγ活性、基因敲除、显性负性构建体或通过过表达构建体增强CaMKIIγ活性表明，活化的CaMKIIγ可使FOXO3a磷酸化。在Jurkat细胞中，活化的CaMKIIγ通过直接或间接磷酸化AKT使FOXO3a磷酸化，将FOXO3a排除在细胞核外并抑制其转录活性。这些结果表明，活化的CaMKIIγ可能在T-ALL白血病发生中起关键作用，靶向CaMKIIγ可能是治疗T-ALL的一种有价值的方法。
