Aberrant activation of CaMKIIγ accelerates chronic myeloid leukemia blast crisis

作者：Gu, Y.; Zheng, W.; Zhang, J.; Gan, X.; Ma, X.; Meng, Z.; Chen, T.; Lu, X.; Wu, Z.; Huang, W.^*; Xu, R.^*

来源：Leukemia, 2016, 30(6): 1282-1289.

DOI：10.1038/leu.2016.53

• CHRONIC MYELOGENOUS LEUKEMIA
• CML STEM-CELLS
• BCR-ABL
• CRITICAL REGULATOR
• BETA-CATENIN
• INHIBITOR
• P27(KIP1)
• GENE
• DETERMINANT
• BERBAMINE

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 II. (CaMKII.). Genetic deletion of CaMKII. greatly inhibits disease progression via selectively impairing the self-renewal of leukemia stem cells (LSCs) in mouse models, whereas overexpression of CaMKII. has the opposite effects. In human CML, phosphorylated CaMKII. abundance is significantly associated with BC. Moreover, CaMKII. phosphorylates and reduces the nuclear cyclin-dependent kinase inhibitor p27Kip1, a critical brake that maintains LSC quiescence. These findings suggest that CaMKII. might be an important switch for the transition of CML BC and identify a unique mechanism by which CaMKII. promotes the self-renewal of LSCs by deceasing nuclear p27Kip1 to wake up dormant LSCs. Therefore, CaMKII. may provide a new therapeutic target to treat CML BC.

• 出版日期2016-6
• 单位浙江大学; 浙江省医学科学院