Expression of genes involved in immune regulation in chronic myeloid leukemia
Keywords:Bạch cầu tủy mạn, klotho, CTLA4, IκB-α, PD1, LAG3 và STAT
Chronic myeloid leukemia (CML) is a blood cancer involved in abnormal proliferation of myeloid cells at all stages of differentiation. Translocation of regions of the BCR and ABL genes, leading to the fusion gene BCR-ABL, which forms the Philadelphia (Ph) chromosome, is the cause of more than 90% of CML. The BCR-ABL protein shows abnormal tyrosine kinase activity, leading to changes in proliferation signals including signal transducer and activator of transcriptions (STATs) and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) and resulting in uncontrolled proliferation of myeloid cells. CTLA-4, PD-1 and LAG3 genes are known as immunosuppressive receptors playing important roles in controlling immune response by inhibiting activity of T helper cells. Klotho gene has anti-aging, anti-inflammatory and anti-cancer functions. STAT signaling pathway genes regulate cancer cell functions by their phosphorylation and IκB-α gene by degradation of its expression. In this study, we conducted experiments to determine mRNA expression of these genes on immune cells in CML patients by using realtime-PCR. Results showed a marked increase in the expression of STAT-1 and STAT-6 signaling genes and a decreased LAG3 expression in CML patients as compared with healthy controls. In addition, other gene expressions such as CTLA4, PD1, klotho, IκB-α, STAT3 and STAT5 were unaltered in CML cells. The abnormal increased expression of STAT1 and STAT6 genes indicated an important role of these signaling genes in regulating activity of immune cells, leading to pathogenesis and development of CML disease. The evidence suggested that STAT-1 and STAT-6 genes could be important and potential markers in early prognosis of CML.
Arzt L, Kothmaier H, Halbwedl I, Quehenberger F, & Popper HH. (2014) Signal transducer and activator of transcription 1 (STAT1) acts like an oncogene in malignant pleural mesothelioma. Virchows Archiv : an international journal of pathology 465: 79-88.
Buchbinder EI, & Desai A. (2016) CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition. American journal of clinical oncology 39: 98-106.
Chen BJ, Dashnamoorthy R, Galera P, et al. (2019a) The immune checkpoint molecules PD-1, PD-L1, TIM-3 and LAG-3 in diffuse large B-cell lymphoma. Oncotarget 10: 2030-2040.
Chen N, Feng L, Lu K, et al. (2019b) STAT6 phosphorylation upregulates microRNA-155 expression and subsequently enhances the pathogenesis of chronic lymphocytic leukemia. Oncology letters 18: 95-100.
Christiansson L, Soderlund S, Svensson E, et al. (2013) Increased level of myeloid-derived suppressor cells, programmed death receptor ligand 1/programmed death receptor 1, and soluble CD25 in Sokal high risk chronic myeloid leukemia. PloS one 8: e55818.
Cochet O, Frelin C, Peyron JF, & Imbert V. (2006) Constitutive activation of STAT proteins in the HDLM-2 and L540 Hodgkin lymphoma-derived cell lines supports cell survival. Cell Signal 18: 449-455.
Hantschel O, Warsch W, Eckelhart E, et al. (2012) BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia. Nature chemical biology 8: 285-293.
He Y, Rivard CJ, Rozeboom L, et al. (2016) Lymphocyte-activation gene-3, an important immune checkpoint in cancer. Cancer science 107: 1193-1197.
Hehlmann R, Hochhaus A, Baccarani M, & European L. (2007) Chronic myeloid leukaemia. Lancet 370: 342-350.
Keir ME, Butte MJ, Freeman GJ, & Sharpe AH. (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26: 677-704.
Leibrock CB, Voelkl J, Kuro OM, Lang F, & Lang UE. (2016) 1,25(OH)2D3 dependent overt hyperactivity phenotype in klotho-hypomorphic mice. Sci Rep 6: 24879.
Lorenzi O, Veyrat-Durebex C, Wollheim CB, et al. (2010) Evidence against a direct role of klotho in insulin resistance. Pflugers Arch 459: 465-473.
Meissl K, Macho-Maschler S, Muller M, & Strobl B. (2017) The good and the bad faces of STAT1 in solid tumours. Cytokine 89: 12-20.
Morotti A, Crivellaro S, Panuzzo C, et al. (2017) IkappaB-alpha: At the crossroad between oncogenic and tumor-suppressive signals. Oncology letters 13: 531-534.
Nair RR, Tolentino JH, & Hazlehurst LA. (2012) Role of STAT3 in Transformation and Drug Resistance in CML. Frontiers in oncology 2: 30.
Okazaki T, Okazaki IM, Wang J, et al. (2011) PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice. The Journal of experimental medicine 208: 395-407.
Rubinek T, Shulman M, Israeli S, et al. (2012) Epigenetic silencing of the tumor suppressor klotho in human breast cancer. Breast cancer research and treatment 133: 649-657.
Saurabh K, Ghalaut VS, Bala J. Chronic myeloid leukemia and ferritin levels. Biomed Biotechnol Res J 2017;1:120-3.
Sayed D, Badrawy H, Gaber N, & Khalaf MR. (2014) p-Stat3 and bcr/abl gene expression in chronic myeloid leukemia and their relation to imatinib therapy. Leuk Res 38: 243-250.
Scheeren FA, Diehl SA, Smit LA, et al. (2008) IL-21 is expressed in Hodgkin lymphoma and activates STAT5: evidence that activated STAT5 is required for Hodgkin lymphomagenesis. Blood 111: 4706-4715.
Schmidt S, & Wolf D. (2009) Role of gene-expression profiling in chronic myeloid leukemia. Expert Rev Hematol 2: 93-103.
Shapiro M, Herishanu Y, Katz BZ, et al. (2017) Lymphocyte activation gene 3: a novel therapeutic target in chronic lymphocytic leukemia. Haematologica 102: 874-882.
Sharma P, & Allison JP. (2015) The future of immune checkpoint therapy. Science 348: 56-61.
Song TL, Nairismagi ML, Laurensia Y, et al. (2018) Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma. Blood 132: 1146-1158.
Wolf I, Levanon-Cohen S, Bose S, et al. (2008) Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Oncogene 27: 7094-7105.
Xuan NT, & Hai NV. (2018) Changes in expression of klotho affect physiological processes, diseases, and cancer. Iranian journal of basic medical sciences 21: 3-8.
Yang H, Bueso-Ramos C, DiNardo C, et al. (2014) Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia 28: 1280-1288.