Activation of CaMKIIγ potentiates T-cell acute lymphoblastic leukemia leukemogenesis via phosphorylating FOXO3a
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Xudong Jiang1,2,*, Zhaoxing Wu1,2,*, Xiaoya Lu1,2,*, Xuzhao Zhang1, Qingfeng Yu1,2, Yichao Gan1,2, Bowen Wu1,2, Ying Xu1,2, Weiwei Zheng3, Lei Zhang1,2, Fei Xu2, An Ma4, Xiaoxian Gan4, Silvia Huang5, Xiaofang Yu2, Wendong Huang6,7 and Rongzhen Xu1,2
1Department 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
2Cancer Institute of Zhejiang University, Hangzhou 310009, China
3Deptartment of Clinical Laboratory of Anhui Provincial Hospital, Anhui Medical University, Hefei 230000, China
4Zhejiang Academy of Medical Sciences, Hangzhou 310009, China
5City of Hope Eugene and Ruth Roberts Summer Student Academy, City of Hope National Medical Center, Duarte, CA 91010, USA
6Molecular Oncology Program and Department of Diabetes Complications and Metabolism, Beckman Research Institute, Duarte, CA 91010, USA
7Irell & Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA 91010, USA
*These authors have contributed equally to this work
Rongzhen Xu, email: [email protected]
Wendong Huang, email: [email protected]
Keywords: T-cell acute lymphoblastic leukemia, leukemogenesis, CaMKIIγ, AKT, FOXO3a
Received: February 17, 2017 Accepted: July 29, 2017 Published: August 24, 2017
Ca2+/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, in vivo 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.
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