title: Aberrant activation of CaMKIIγ accelerates chronic myeloid leukemia blast crisis.
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.
authors.affiliation: 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.|Cancer Institute of Zhejiang University, Hangzhou, China.|Molecular Oncology Program and Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Gu
authors.affiliation: 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.|Cancer Institute of Zhejiang University, Hangzhou, China.
authors.forename: W
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Cancer Institute of Zhejiang University, Hangzhou, China.|Molecular Oncology Program and Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Molecular Oncology Program and Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.|Zhejiang Academy of Medical Sciences, Hangzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Gan
authors.affiliation: Molecular Oncology Program and Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.|Irell and Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Ma
authors.affiliation: Molecular Oncology Program and Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.|Irell and Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Meng
authors.affiliation: Cancer Institute of Zhejiang University, Hangzhou, China.
authors.forename: T
authors.initials: T
authors.lastname: Chen
authors.affiliation: 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.|Cancer Institute of Zhejiang University, Hangzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Lu
authors.affiliation: 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.|Cancer Institute of Zhejiang University, Hangzhou, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Molecular Oncology Program and Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.|Irell and Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Huang
authors.affiliation: 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.|Cancer Institute of Zhejiang University, Hangzhou, China.|Molecular Oncology Program and Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Xu
mesh_terms: D000818:Animals; D001752:Blast Crisis / Q000209:etiology* / Q000473:pathology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D000066673:Cell Self Renewal; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D051379:Mice; D014411:Neoplastic Stem Cells; D010766:Phosphorylation
chemical_list: C436291:CDKN1B protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2