Activation of CaMKIIγ potentiates T-cell acute lymphoblastic leukemia leukemogenesis via phosphorylating FOXO3a

Xudong Jiang; Zhaoxing Wu; Xiaoya Lu; Xuzhao Zhang; Qingfeng Yu; Yichao Gan; Bowen Wu; Ying Xu; Weiwei Zheng; Lei Zhang; Fei Xu; An Ma; Xiaoxian Gan; Silvia Huang; Xiaofang Yu; Wendong Huang; Rongzhen Xu

doi:10.18632/oncotarget.20504

Activation of CaMKIIγ potentiates T-cell acute lymphoblastic leukemia leukemogenesis via phosphorylating FOXO3a

Oncotarget. 2017 Aug 24;8(43):75050-75064. doi: 10.18632/oncotarget.20504. eCollection 2017 Sep 26.

Authors

Xudong Jiang^{1

2}, Zhaoxing Wu^{1

2}, Xiaoya Lu^{1

2}, Xuzhao Zhang¹, Qingfeng Yu^{1

2}, Yichao Gan^{1

2}, Bowen Wu^{1

2}, Ying Xu^{1

2}, Weiwei Zheng³, Lei Zhang^{1

2}, Fei Xu², An Ma⁴, Xiaoxian Gan⁴, Silvia Huang⁵, Xiaofang Yu², Wendong Huang^{6

7}, Rongzhen Xu^{1

2}

Affiliations

¹ 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.
² Cancer Institute of Zhejiang University, Hangzhou, 310009 China.
³ Deptartment of Clinical Laboratory of Anhui Provincial Hospital, Anhui Medical University, Hefei 230000, China.
⁴ Zhejiang Academy of Medical Sciences, Hangzhou 310009, China.
⁵ City of Hope Eugene and Ruth Roberts Summer Student Academy, City of Hope National Medical Center, Duarte, CA 91010, USA.
⁶ Molecular Oncology Program and Department of Diabetes Complications and Metabolism, Beckman Research Institute, Duarte, CA 91010, USA.
⁷ Irell & Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA 91010, USA.

Abstract

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.

Keywords: AKT; CaMKIIγ; FOXO3a; T-cell acute lymphoblastic leukemia; leukemogenesis.