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Chronic myelogenous leukemia

Aberrant activation of CaMKIIγ accelerates chronic myeloid leukemia blast crisis

Leukemia volume 30, pages 1282–1289 (2016)Cite this article

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Abstract

Blast crisis (BC) is the final deadly phase of chronic myeloid leukemia (CML), but its molecular basis remains poorly understood. Here, we show that CML BC is regulated by calcium-calmodulin-dependent kinase IIγ (CaMKIIγ). Genetic deletion of CaMKIIγ greatly inhibits disease progression via selectively impairing the self-renewal of leukemia stem cells (LSCs) in mouse models, whereas overexpression of CaMKIIγ has the opposite effects. In human CML, phosphorylated CaMKIIγ abundance is significantly associated with BC. Moreover, CaMKIIγ phosphorylates and reduces the nuclear cyclin-dependent kinase inhibitor p27Kip1, a critical brake that maintains LSC quiescence. These findings suggest that CaMKIIγ might be an important switch for the transition of CML BC and identify a unique mechanism by which CaMKIIγ promotes the self-renewal of LSCs by deceasing nuclear p27Kip1 to wake up dormant LSCs. Therefore, CaMKIIγ may provide a new therapeutic target to treat CML BC.

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Acknowledgements

This work was supported, in part, by the National Natural Science Foundation of China (81270601, 81328016, 81470306 and 81201869), Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents, NCI R01CA139158 from the National Cancer Institute, Zhejiang provincial natural science foundation of China (Y2110018, LY14H160032), Zhejiang Province Department of Education (Y201330049), Leukemia Research Innovative Team of Zhejiang Province (2011R50015) and Science Technology Department of Zhejiang Province (2013C33135). We thank Dr Eric N Olson from the University of Texas Southwestern Medical Center and Dr Johannes Backs from the University of Heidelberg for providing the CAMKIIγ−/− mice.

Author contributions

RZX and WDH conceived the study, initiated, designed and supervised the experiments and wrote the manuscript. YG, WWZ, JWZ, XXG, XXM, ZPM, TC, XYL and ZXW performed experiments.

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Author notes

  1. Y Gu, W Zheng and J Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

    Y Gu, W Zheng, X Lu, Z Wu & R Xu

  2. Cancer Institute of Zhejiang University, Hangzhou, China

    Y Gu, W Zheng, J Zhang, T Chen, X Lu, Z Wu & R Xu

  3. Molecular Oncology Program and Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA

    Y Gu, J Zhang, X Gan, X Ma, Z Meng, W Huang & R Xu

  4. Zhejiang Academy of Medical Sciences, Hangzhou, China

    X Gan

  5. Irell and Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA, USA

    X Ma, Z Meng & W Huang

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Correspondence to W Huang or R Xu.

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Gu, Y., Zheng, W., Zhang, J. et al. Aberrant activation of CaMKIIγ accelerates chronic myeloid leukemia blast crisis. Leukemia 30, 1282–1289 (2016). https://doi.org/10.1038/leu.2016.53

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