CaMKIIγ regulates the viability and self-renewal of acute myeloid leukaemia stem-like cells by the Alox5/NF-κB pathway
Jiang-Hua Cheng
School of Tea & Food Science, Anhui Agricultural University, Hefei, China
Institute of Agro-products Processing Research, Anhui Academy of Agricultural Sciences, Hefei, China
Search for more papers by this authorWen-Jing Zhang
Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
Search for more papers by this authorJun-Feng Zhu
Department of Hematology, First Affiliated Hospital, Bengbu Medical College, Bengbu, China
Search for more papers by this authorDi Cui
School of Laboratory Medicine, Bengbu Medical College, Bengbu, China
Search for more papers by this authorKai-Di Song
Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
Search for more papers by this authorPing Qiang
Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
Search for more papers by this authorChuan-Zhong Mei
School of Laboratory Medicine, Bengbu Medical College, Bengbu, China
Search for more papers by this authorZheng-Chao Nie
Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
Search for more papers by this authorBang-Sheng Ding
Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
Search for more papers by this authorCorresponding Author
Zhong Han
Department of Clinical Laboratory, Shengzhou People’s Hospital, Shenzhou Branch of the First Affiliated Hospital of Zhejiang University, Shengzhou, China
Correspondence
Wei-Wei Zheng, Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Email: [email protected]
Zhi-En Ding, School of Tea & Food Science, Anhui Agricultural University, Hefei, China.
Email: [email protected]
Zhong Han, Department of Clinical Laboratory, Shengzhou People’s Hospital, Shenzhou Branch of the First Affiliated Hospital of Zhejiang University, Shengzhou, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Zhi-En Ding
School of Tea & Food Science, Anhui Agricultural University, Hefei, China
Department of Biology and Food Engineering, Bozhou University, Bozhou, China
Correspondence
Wei-Wei Zheng, Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Email: [email protected]
Zhi-En Ding, School of Tea & Food Science, Anhui Agricultural University, Hefei, China.
Email: [email protected]
Zhong Han, Department of Clinical Laboratory, Shengzhou People’s Hospital, Shenzhou Branch of the First Affiliated Hospital of Zhejiang University, Shengzhou, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Wei-Wei Zheng
Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
Correspondence
Wei-Wei Zheng, Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Email: [email protected]
Zhi-En Ding, School of Tea & Food Science, Anhui Agricultural University, Hefei, China.
Email: [email protected]
Zhong Han, Department of Clinical Laboratory, Shengzhou People’s Hospital, Shenzhou Branch of the First Affiliated Hospital of Zhejiang University, Shengzhou, China.
Email: [email protected]
Search for more papers by this authorJiang-Hua Cheng
School of Tea & Food Science, Anhui Agricultural University, Hefei, China
Institute of Agro-products Processing Research, Anhui Academy of Agricultural Sciences, Hefei, China
Search for more papers by this authorWen-Jing Zhang
Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
Search for more papers by this authorJun-Feng Zhu
Department of Hematology, First Affiliated Hospital, Bengbu Medical College, Bengbu, China
Search for more papers by this authorDi Cui
School of Laboratory Medicine, Bengbu Medical College, Bengbu, China
Search for more papers by this authorKai-Di Song
Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
Search for more papers by this authorPing Qiang
Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
Search for more papers by this authorChuan-Zhong Mei
School of Laboratory Medicine, Bengbu Medical College, Bengbu, China
Search for more papers by this authorZheng-Chao Nie
Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
Search for more papers by this authorBang-Sheng Ding
Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
Search for more papers by this authorCorresponding Author
Zhong Han
Department of Clinical Laboratory, Shengzhou People’s Hospital, Shenzhou Branch of the First Affiliated Hospital of Zhejiang University, Shengzhou, China
Correspondence
Wei-Wei Zheng, Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Email: [email protected]
Zhi-En Ding, School of Tea & Food Science, Anhui Agricultural University, Hefei, China.
Email: [email protected]
Zhong Han, Department of Clinical Laboratory, Shengzhou People’s Hospital, Shenzhou Branch of the First Affiliated Hospital of Zhejiang University, Shengzhou, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Zhi-En Ding
School of Tea & Food Science, Anhui Agricultural University, Hefei, China
Department of Biology and Food Engineering, Bozhou University, Bozhou, China
Correspondence
Wei-Wei Zheng, Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Email: [email protected]
Zhi-En Ding, School of Tea & Food Science, Anhui Agricultural University, Hefei, China.
Email: [email protected]
Zhong Han, Department of Clinical Laboratory, Shengzhou People’s Hospital, Shenzhou Branch of the First Affiliated Hospital of Zhejiang University, Shengzhou, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Wei-Wei Zheng
Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
Correspondence
Wei-Wei Zheng, Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Email: [email protected]
Zhi-En Ding, School of Tea & Food Science, Anhui Agricultural University, Hefei, China.
Email: [email protected]
Zhong Han, Department of Clinical Laboratory, Shengzhou People’s Hospital, Shenzhou Branch of the First Affiliated Hospital of Zhejiang University, Shengzhou, China.
Email: [email protected]
Search for more papers by this authorAbstract
Acute myeloid leukaemia (AML) is a frequently fatal malignant disease of haematopoietic stem and progenitor cells. The molecular and phenotypic characteristics of AML are highly heterogeneous. Our previous study concluded that CaMKIIγ was the trigger of chronic myeloid leukaemia progression from the chronic phase to blast crisis, but how CaMKIIγ influences AML stem-like cells remains elusive. In this study, we found that CaMKIIγ was overexpressed in AML patients and AML cell lines, as measured by qRT-PCR and Western blot assays. Moreover, CaMKIIγ decreased when the disease was in remission. Using an shRNA lentivirus expression system, we established CaMKIIγ stable-knockdown AML cell lines and found that knockdown of CaMKIIγ inhibited the viability and self-renewal of AML stem-like cell lines. Additionally, the ratio of CD34+ AML cell lines decreased, and CaMKIIγ knockdown induced the downregulation of Alox5 levels. We further detected downstream molecules of the Alox5/NF-κB pathway and found that c-myc and p-IκBα decreased while total IκBα remained normal. In conclusion, our study describes a new role for CaMKIIγ as a stem-like cell marker that is highly regulated by the Alox5/NF-κB pathway in AML stem-like cells. CaMKIIγ can participate in the viability and self-renewal of AML stem-like cells by regulating the Alox5/NF-κB pathway.
CONFLICTS OF INTEREST
The authors declare no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
All data included in this study are available upon request by contact with the corresponding author.
REFERENCES
- 1Giri S, Pathak R, Aryal MR, et al. Impact of hospital volume on outcomes of patients undergoing chemotherapy for acute myeloid leukemia: a matched cohort study. Blood. 2015; 125(21): 3359-3360.
- 2Bekdash M, Darwish M, Timsah Z, et al. Phospho-MEK1/2 and uPAR expression determine sensitivity of AML blasts to a urokinase-activated anthrax lethal toxin (PrAgU2/LF). Transl Oncol. 2015; 8(5): 347-357.
- 3Sands WA, Copland M, Wheadon H. Targeting self-renewal pathways in myeloid malignancies. Cell Commun Signal. 2013; 11(1): 33.
- 4Raffel S, Trumpp A. miR-126 drives quiescence and self-renewal in leukemic stem cells. Cancer Cell. 2016; 29(2): 133-135.
- 5Martelli AM, Evangelisti C, Chiarini F, et al. The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients. Oncotarget. 2010; 1(2): 89-103.
- 6Eppert K, Takenaka K. Eric R Lechman, stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med. 2011; 17(9): 1086-1093.
- 7Erb U, Megaptche AP, Gu X, et al. CD44 standard and CD44v10 isoform expression on leukemia cells distinctly influences niche embedding of hematopoietic stem cells. J Hematol Oncol. 2014; 31(7): 29.
- 8Somervaille TCP, Cleary ML. Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia.Cancer. Cell. 2006; 10(4): 257-268.
- 9Dick JE. Stem cell concepts renew cancer research. Blood. 2008; 112(13): 4793-4807.
- 10Wang Y, Krivtsov AV, Sinha AU, et al. The Wnt/-catenin pathway is required for the development of leukemia stem cells in AML. Science. 2010; 327(5973): 1650-1653.
- 11Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2016; 36: 1461.
- 12Bui JD, Calbo S, Hayden-Martinez K, Kane LP, Gardner P, Hedrick SM. A role for CaMKII in T cell memory. Cell. 2000; 100: 457-467.
- 13Hook SS, Means AR. Ca(2+)/CaM-dependent kinases: from activation to function. Annu Rev Pharmacol Toxicol. 2001; 41: 471-505.
- 14Nowycky MC, Thomas AP. Intracellular calcium signaling. J Cell Sci. 2002; 115(Pt 19): 3715-3716.
- 15Orrenius S, Zhivotovsky B, Nicotera P. Regulation of cell death:the calcium-apoptosis link. Nat Rev Mol Cell Biol. 2003; 4(7): 552-565.
- 16Colomer J, Means AR. Physiological roles of the Ca2+/CaM-dependent protein kinase cascade in health and disease. Subcell Biochem. 2007; 45: 169-214.
- 17Meng Z, Li T, Ma X, et al. Berbamine inhibits the growth of liver cancer cells and cancer-initiating cells by targeting Ca(2)(+)/calmodulin-dependent protein kinase II. Mol Cancer Ther. 2013; 12: 2067-2077.
- 18Gu Y, Zheng W, Zhang J, et al. Aberrant activation of CaMKIIgamma accelerates chronic myeloid leukemia blast crisis. Leukemia. 2016; 30: 1282-1289.
- 19Si J, Collins SJ. Activated Ca 2+ /calmodulin-dependent protein kinase IIgamma is a critical regulator of myeloid leukemia cell proliferation. Cancer Res. 2008; 68: 3733-3742.
- 20Lin MY, Zal T, Chen IL, et al. A pivotal role for the multifunctional calcium/calmodulin-dependent protein kinase II in T cells: from activation to unresponsiveness. J Immunol. 2005; 174: 5583-5592.
- 21Soberman RJ, Christmas P. The organization and consequences of eicosanoid signaling. J Clin Invest. 2003; 111(8): 1107-1113.
- 22Lewis RA, Austen KF, Soberman RJ. Leukotrienes and other products of the 5-lipoxygenase pathway. Biochemistry and relation to pathobiology in human diseases. N Engl J Med. 1990; 323(10): 645-655.
- 23Kim HA, Lee KH, Lee BH. Neuroprotective effect of melatonin against kainic acid-induced oxidative injury in hippocampal slice culture of rats. Int J Mol Sci. 2014; 15: 5940-5951.
- 24Enyedi B, Jelcic M, Niethammer P. The cell nucleus serves as a mechanotransducer of tissue damage-induced inflammation. Cell. 2016; 165: 1160-1170.
- 25Poczobutt JM, Nguyen TT, Hanson D, et al. Deletion of 5-lipoxygenase in the tumor microenvironment promotes lung cancer progression and metastasis through regulating t cell recruitment. J Immunol. 2016; 196(2): 891-901.
- 26Sarveswaran S, Chakraborty D, Chitale D, et al. Inhibition of 5-lipoxygenase selectively triggers disruption of c-Myc signaling in prostate cancer cells. J Biol Chem. 2015; 290(8): 4994-5006.
- 27Zhou GX, Ding XL, Wu SB, et al. Inhibition of 5-lipoxygenase triggers apoptosis in pancreatic cancer cells. Oncol Rep. 2015; 33(2): 661-668.
- 28Zhao Y, Wang W, Wang Q, et al. Lipid metabolism enzyme 5-LOX and its metabolite LTB4 are capable of activating transcription factor NF-κB in hepatoma cells. Biochem Biophys Res Commun. 2012; 418(4): 647-651.
- 29Chen Y, Hu Y, Zhang H, et al. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nat Genet. 2009; 41(7): 783-792.
- 30Yan M, Kanbe E, Peterson LF, et al. A previously unidentified alternatively spliced isoform of t(8;21) transcript promotes leukemogenesis. Nat Med. 2006; 12(8): 945-949.
- 31Neff T, Sinha AU, Kluk MJ, et al. Polycomb repressive complex 2 is required for MLL-AF9 leukemia. Proc Natl Acad Sci USA. 2012; 109(13): 5028-5033.
Citing Literature
