Articles

Mesenchymal Stem Cells as a Cell-Based Therapeutic Strategy Targeting the Telomerase Activity of KG1 Acute Myeloid Leukemia Cells

Abstract

A predominant challenge in the discovery approach to curative leukemia is investigating the effect of mesenchymal stem cells (MSCs) on leukemic cells. We aimed to investigate the role of MSCs in targeting telomerase enzyme and consequently telomere length of leukemic cells. For this purpose, the KG1 cell as leukemia cell line was co-cultured with MSCs in the trans-well system. After seven days of co-culture, KG1 cells were collected, and telomerase activity, telomere length, and hTERT gene expression were analyzed by PCR-ELISA TRAP assay and real-time PCR, respectively. Also, the potentially involved ERK pathway was analyzed at gene and protein levels by real time PCR and flow cytometry, respectively. It was found that MSCs caused a significant decrease in telomerase activity, telomere length, and hTERT gene expression. The following results showed that MSCs resulted in a significant decrease in the ERK expression levels. It can be concluded that the co-culture of MSCs with KG1 cells be involved in the telomerase targeting via ERK signaling pathways. This study concluded that the co-culture of MSCs with AML leukemic cells could secrete a significant amount of cytokines that cause to inhibit the proliferation of AML cell lines via ERK signaling pathway. The recognition of cytokines as well as growth factors involved in the anti-proliferative effect of MSCs requires further investigation. This effect as a therapeutic strategy could be considered in the basic experimental studies.

1. Shahjahani M, Khodadi E, Seghatoleslami M, Asl JM, Golchin N, Zaieri ZD, et al. Rare cytogenetic abnormalities and alteration of microRNAs in acute myeloid leukemia and response to therapy. Oncology reviews. 2015;9(1).
2. Rajabzadeh N, Fathi E, and Farahzadi R. Stem cell-based regenerative medicine. Stem Cell Investigation. 2019;6.
3. Manabe A, Coustan-Smith E, Behm FG, Raimondi SC, and Campana D. Bone marrow-derived stromal cells prevent apoptotic cell death in B-lineage acute lymphoblastic leukemia. Blood. 1992;79(9):2370-2377.
4. Zhu Y, Sun Z, Han Q, Liao L, Wang J, Bian C, et al. Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1. Leukemia. 2009;23(5):925.
5. Calado RT, Regal JA, Hills M, Yewdell WT, Dalmazzo LF, Zago MA, et al. Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia. Proceedings of the National Academy of Sciences. 2009;106(4):1187-1192.
6. Calado RT and Young NS. Telomere diseases. New England Journal of Medicine. 2009;361(24):2353-2365.
7. Blackburn EH, Epel ES, and Lin J. Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection. Science. 2015;350(6265):1193-1198.
8. Fathi E and Farahzadi R. Zinc sulphate mediates the stimulation of cell proliferation of rat adipose tissue-derived mesenchymal stem cells under high intensity of EMF exposure. Biological trace element research. 2018;184(2):529-535.
9. Fathi E, Farahzadi R, and Sheikhzadeh N. Immunophenotypic characterization, multi-lineage differentiation and aging of zebrafish heart and liver tissue-derived mesenchymal stem cells as a novel approach in stem cell-based therapy. Tissue and Cell. 2019;57:15-21.
10. O'Callaghan NJ and Fenech M. A quantitative PCR method for measuring absolute telomere length. Biological procedures online. 2011;13(1):3.
11. Aminizadeh N, Tiraihi T, Mesbah-Namin SA, and Taheri T. Stimulation of cell proliferation by glutathione monoethyl ester in aged bone marrow stromal cells is associated with the assistance of TERT gene expression and telomerase activity. In Vitro Cellular & Developmental Biology-Animal. 2016;52(7):772-781.
12. Faezizadeh Z, Mesbah-Namin SAR, and Allameh A. The effect of silymarin on telomerase activity in the human leukemia cell line K562. Planta medica. 2012;78(09):899-902.
13. Liang R, Huang G-s, Wang Z, Chen X-q, Bai Q-x, Zhang Y-q, et al. Effects of human bone marrow stromal cell line (HFCL) on the proliferation, differentiation and apoptosis of acute myeloid leukemia cell lines U937, HL-60 and HL-60/VCR. International journal of hematology. 2008;87(2):152-166.
14. Tian K, Yang S, Ren Q, Han Z, Lu S, Ma F, et al. p38 MAPK contributes to the growth inhibition of leukemic tumor cells mediated by human umbilical cord mesenchymal stem cells. Cellular Physiology and Biochemistry. 2010;26(6):799-808.
15. Larijani B, NASLI EE, Amini P, Nikbin B, Alimoghaddam K, Amiri S, et al. Stem cell therapy in treatment of different diseases. 2012.
16. Gholizadeh-Ghaleh Aziz S, Fathi E, Rahmati-Yamchi M, Akbarzadeh A, Fardyazar Z, and Pashaiasl M. An update clinical application of amniotic fluid-derived stem cells (AFSCs) in cancer cell therapy and tissue engineering. Artificial cells, nanomedicine, and biotechnology. 2017;45(4):765-774.
17. Kishtagari A and Watts J. Biological and clinical implications of telomere dysfunction in myeloid malignancies. Therapeutic advances in hematology. 2017;8(11):317-326.
18. Townsley DM, Dumitriu B, and Young NS. Bone marrow failure and the telomeropathies. Blood. 2014;124(18):2775-2783.
19. Brümmendorf T and Balabanov S. Telomere length dynamics in normal hematopoiesis and in disease states characterized by increased stem cell turnover. Leukemia. 2006;20(10):1706-1716.
20. Capraro V, Zane L, Poncet D, Perol D, Galia P, Preudhomme C, et al. Telomere deregulations possess cytogenetic, phenotype, and prognostic specificities in acute leukemias. Experimental hematology. 2011;39(2):195-202. e2.
21. Lewis TS, Shapiro PS, and Ahn NG. Signal transduction through MAP kinase cascades. Adv Cancer Res. 1998;74:49-139.
22. Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, and Papamichail M. Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells. 2006;24(1):74-85.
23. Sebolt-Leopold JS and Herrera R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer. 2004;4(12):937-47.
24. Zhang HM and Zhang LS. Influence of human bone marrow mesenchymal stem cells on proliferation of chronic myeloid leukemia cells. Ai Zheng. 2009;28(1):29-32.
25. Kogler G, Radke TF, Lefort A, Sensken S, Fischer J, Sorg RV, et al. Cytokine production and hematopoiesis supporting activity of cord blood-derived unrestricted somatic stem cells. Exp Hematol. 2005;33(5):573-83.
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IssueVol 60, No 2 (2022) QRcode
SectionArticles
DOI https://doi.org/10.18502/acta.v60i2.8817
Keywords
Mesenchymal stem cells Acute myeloid leukemia Telomerase activity Telomere length ERK signaling pathways
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How to Cite
1.
Fathi E, Farahzadi R. Mesenchymal Stem Cells as a Cell-Based Therapeutic Strategy Targeting the Telomerase Activity of KG1 Acute Myeloid Leukemia Cells. Acta Med Iran. 2022;60(2):71-77.