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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References
Hantschel O, Superti-Furga G . Regulation of the c-Abl and Bcr-Abl tyrosine kinases. Nat Rev Mol Cell Biol 2004; 5: 33–44.
Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci USA 2006; 103: 2794–2799.
Zheng C, Li L, Haak M, Brors B, Frank O, Giehl M et al. Gene expression profiling of CD34+ cells identifies a molecular signature of chronic myeloid leukemia blast crisis. Leukemia 2006; 20: 1028–1034.
Lucas CM, Harris RJ, Giannoudis A, Copland M, Slupsky JR, Clark RE . Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression. Blood 2011; 117: 6660–6668.
Najfeld V . Development of t(8;21) and RUNX1-RUNX1T1 in the Philadelphia-positive clone of a patient with chronic myelogenous leukemia: additional evidence for multiple steps involved in disease progression. Cancer Genet 2011; 204: 165–170.
Sachs RK, Johnsson K, Hahnfeldt P, Luo J, Chen A, Hlatky L . A multicellular basis for the origination of blast crisis in chronic myeloid leukemia. Cancer Res 2011; 71: 2838–2847.
Yamada O, Ozaki K, Furukawa T, Machida M, Wang YH, Motoji T et al. Activation of STAT5 confers imatinib resistance on leukemic cells through the transcription of TERT and MDR1. Cell Signal 2011; 23: 1119–1127.
Makishima H, Jankowska AM, McDevitt MA, O'Keefe C, Dujardin S, Cazzolli H et al. CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations and additional chromosomal aberrations constitute molecular events in chronic myelogenous leukemia. Blood 2011; 117: e198–e206.
Griner LN, Reuther GW . Aggressive myeloid leukemia formation is directed by the Musashi 2/Numb pathway. Cancer Biol Ther 2010; 10: 979–982.
Soverini S, Score J, Iacobucci I, Poerio A, Lonetti A, Gnani A et al. IDH2 somatic mutations in chronic myeloid leukemia patients in blast crisis. Leukemia 2011; 25: 178–181.
Ito T, Kwon HY, Zimdahl B, Congdon KL, Blum J, Lento WE et al. Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature 2010; 466: 765–768.
Nakahara F, Kitaura J, Uchida T, Nishida C, Togami K, Inoue D et al. Hes1 promotes blast crisis in chronic myelogenous leukemia through MMP-9 upregulation in leukemic cells. Blood 2014; 123: 3932–3942.
Herrmann H, Sadovnik I, Cerny-Reiterer S, Rülicke T, Stefanzl G, Willmann M et al. Dipeptidylpeptidase IV (CD26) defines leukemic stem cells (LSC) in chronic myeloid leukemia. Blood 2014; 123: 3951–3962.
Ng KP, Manjeri A, Lee KL, Huang W, Tan SY, Chuah CT et al. Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition. Blood 2014; 123: 3316–3326.
Stuart SA, Minami Y, Wang JY . The CML stem cell: evolution of the progenitor. Cell Cycle 2009; 8: 1338–1343.
Sloma I, Jiang X, Eaves AC, Eaves CJ . Insights into the stem cells of chronic myeloid leukemia. Leukemia 2010; 24: 1823–1833.
Rizo A, Horton SJ, Olthof S, Dontje B, Ausema A, van Os R et al. BMI1 collaborates with BCR-ABL in leukemic transformation of human CD34+ cells. Blood 2010; 116: 4621–4630.
Hurtz C, Hatzi K, Cerchietti L, Braig M, Park E, Kim YM et al. BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. J Exp Med 2011; 208: 2163–2174.
Minami Y, Stuart SA, Ikawa T, Jiang Y, Banno A, Hunton IC et al. BCR-ABL-transformed GMP as myeloid leukemic stem cells. Proc Natl Acad Sci USA 2008; 105: 17967–17972.
Neering SJ, Bushnell T, Sozer S, Ashton J, Rossi RM, Wang PY et al. Leukemia stem cells in a genetically defined murine model of blast-crisis CML. Blood 2007; 110: 2578–2585.
Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL et al. Granulocyte–macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004; 351: 657–667.
Sengupta A, Banerjee D, Chandra S, Banerji SK, Ghosh R, Roy R et al. Deregulation and cross talk among Sonic hedgehog, Wnt, Hox and Notch signaling in chronic myeloid leukemia progression. Leukemia 2007; 21: 949–955.
Si J, Collins SJ . Activated Ca2+/calmodulin-dependent protein kinase IIgamma is a critical regulator of myeloid leukemia cell proliferation. Cancer Res 2008; 68: 3733–3742.
Si J, Mueller L, Collins SJ . CaMKII regulates retinoic acid receptor transcriptional activity and the differentiation of myeloid leukemia cells. J Clin Invest 2007; 117: 1412–1421.
Xu R, Dong Q, Yu Y, Zhao X, Gan X et al. Berbamine: a novel inhibitor of bcr/abl fusion gene with potent anti-leukemia activity. Leuk Res 2006; 30: 17–23.
Xie J, Ma T, Gu Y, Zhang X, Qiu X, Zhang L et al. Berbamine derivatives: a novel class of compounds for anti-leukemia activity. Eur J Med Chem 2009; 44: 3293–3298.
Gu Y, Chen T, Meng Z, Gan Y, Xu X, Lou G et al. CaMKIIγ, a critical regulator of CML stem/progenitor cells, is a target of the natural product berbamine. Blood 2012; 120: 4829–4839.
Hu Y, Chen Y, Douglas L, Li S . β-Catenin is essential for survival of leukemia stem cells in sensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia. Leukemia 2009; 23: 109–116.
Zhao C, Blum J, Chen A, Kwon HY, Jung SH, Cook JM et al. Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 2007; 12: 528–541.
Chu S, McDonald T, Bhatia R . Role of BCR-ABL-Y177-mediated p27kip1 phosphorylation and cytoplasmic localization in enhanced proliferation of chronic myeloid leukemia progenitors. Leukemia 2010; 24: 779–787.
Jain MV, Jangamreddy JR, Grabarek J, Schweizer F, Klonisch T, Cieślar-Pobuda A et al. Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21(Waf1/Cip1) and p27(kip1). Cell Cycle 2015; 14: 2109–2120.
Zhang J, Seet CS, Sun C, Li J, You D, Volk A et al. p27kip1 maintains a subset of leukemia stem cells in the quiescent state in murine MLL-leukemia. Mol Oncol 2013; 7: 1069–1082.
Zhang W, Tan W, Wu X, Poustovoitov M, Strasner A, Li W, Borcherding N et al. A NIK-IKKα module expands ErbB2-induced tumor-initiating cells by stimulating nuclear export of p27/Kip1. Cancer Cell 2013; 23: 647–659.
Besson A, Hwang HC, Cicero S, Donovan SL, Gurian-West M, Johnson D et al. Discovery of an oncogenic activity in p27Kip1 that causes stem cell expansion and a multiple tumor phenotype. Genes Dev 2007; 21: 1731–1746.
Menchón C, Edel MJ, Izpisua Belmonte JC . The cell cycle inhibitor p27Kip1 controls self-renewal and pluripotency of human embryonic stem cells by regulating the cell cycle, Brachyury and Twist. Cell Cycle 2011; 10: 1435–1447.
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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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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DOI: https://doi.org/10.1038/leu.2016.53
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