The Role of Pomalidomide-Based Epigenetic Effect on DNMT Genes Expression in Myeloma Cell Line
Multiple myeloma (MM) is clonal B-cell malignancy characterized by the progressive proliferation of malignant plasma cells and accumulation of monoclonal immunoglobulin (M-spike) in blood and urine. Pomalidomide is an immunomodulatory agent which has potentially suppressed myeloma cell progression, especially in drug-resistant cases. As epigenetic modifications have an important role in gene regulation and because of the revealing role of DNA-Methyltransferase 1 (DNMT1) overexpression in myeloma pathogenesis, in this study DNMT1, 3a and 3b genes expression of U266 myeloma cell line treated with pomalidomide have been evaluated. In this study after treatment of U266 cells with 1 μM pomalidomide for 48 hours, total RNA extraction and cDNA synthesis was performed. Gene expression of DNMT1, 3a and 3b has been evaluated using real time PCR technique. The result of this study show that pomalidomide can downregulate the expression of DNMT1, 3a, and 3b in 48 hours of treatment as 0.049, 0.058 and 0.055, respectively as comparing with untreated control (P<0.05). Based on these results we conclude that pomalidomide has desired effect on epigenetic modification by downregulation of DNMTs genes expression and has been considered as an effective drug for inhibition of myeloma proliferation.
Lemaire, M.; Deleu, S.; de Bruyne, E.; van Valckenborgh, E.; Menu, E.; Vanderkerken, K. The microenvironment and molecular biology of the multiple myeloma tumor. Adv. Cancer Res. 2012, 110, 19–42.
Bruyne, E.; Maes, K.; Deleu, S.; Valckenborgh, E.; Menu, E.; Broek, I.; Fraczek, J.; Grunsven, L.; Rogiers, V.; Jernberg-Wiklund, H.; et al. Epigenetic regulation of myeloma within its bone marrow microenvironment. In Advances in Biology and Therapy of Multiple Myeloma; Munshi, N.C., Anderson, K.C., Eds.; Springer: New York, NY, USA, 2013; pp. 255–282.
Becker, N. Epidemiology of multiple myeloma. Recent Results Cancer Res. 2011, 183, 25–35.
Raab, M.S.; Podar, K.; Breitkreutz, I.; Richardson, P.G.; Anderson, K.C. Multiple myeloma. Lancet 2009, 374, 324–339.
Mahindra, A.; Hideshima, T.; Anderson, K.C. Multiple myeloma: Biology of the disease. Blood Rev. 2011, 24, S5–S11.
Uchiyama H, Barut BA, Mohrbacher AF, Chauhan D, Anderson KC. Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates interleukin-6 secretion. Blood 1993; 82: 3712–3720.
Gupta D, Treon SP, Shima Y, Hideshima T, Podar K, Tai YT et al. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia 2001; 15: 1950–1961.
Michigami T, Shimizu N, Williams PJ, Niewolna M, Dallas SL, Mundy GR et al. Cell–cell contact between marrow stromal cells and myeloma cells via VCAM-1 and alpha(4)beta(1)-integrin enhances production of osteoclast-stimulating activity. Blood 2000; 96: 1953–1960.
Barille-Nion S, Barlogie B, Bataille R, Bergsagel PL, Epstein J, Fenton RG et al. Advances in biology and therapy of multiple myeloma. Hematology 2003, 248–278.
Hayashi T, Hideshima T, Anderson KC. Novel therapies for multiple myeloma. Br J Haematol 2003; 120: 10–17.
Corre J, Mahtouk K, Attal M, Gadelorge M, Huynh A, Fleury-Cappellesso S, Danho
C, Laharrague P, Klein B, Rème T, Bourin P. Bone marrow mesenchymal stem cells are abnormal in multiple myeloma. Leukemia. 2007 May;21(5):1079-88.
Moreaux J, Rème T, Leonard W, Veyrune JL, Requirand G, Goldschmidt H, Hose D,
Klein B. Development of gene expression-based score to predict sensitivity of
multiple myeloma cells to DNA methylation inhibitors. Mol Cancer Ther. 2012 Dec;11(12):2685-92.
Wang LD, Wagers AJ. Dynamic niches in the origination and differentiation of haematopoietic stem cells. Nat Rev Mol Cell Biol 2011;12:643-55.
Bollati V, Fabris S, Pegoraro V, Ronchetti D, Mosca L, Deliliers GL, Motta V, Bertazzi PA, Baccarelli A, Neri A. Differential repetitive DNA methylation in multiple myeloma molecular subgroups. Carcinogenesis. 2009 Aug;30(8):1330-5. 13.
Görgün G, Calabrese E, Soydan E, Hideshima T, Perrone G, Bandi M, Cirstea D, Santo L, Hu Y, Tai YT, Nahar S, Mimura N, Fabre C, Raje N, Munshi N, Richardson P, Anderson KC. Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma. Blood.
Gnyszka A, Jastrzebski Z, Flis S. DNA methyltransferase inhibitors and their emerging role in epigenetic therapy of cancer. Anticancer Res. 2013
Zhu YX, Kortuem KM, Stewart AK. Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma. Leuk Lymphoma. 2013 Apr;54(4):683-7.
Lu QY, Zhang ZC, Hong XL. Expression of DNA methyltransferase in myeloma U266 cells and its significance. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2011 Dec;19(6):1429-31.
Zhou W, Chen H, Hong X, Niu X, Lu Q. Knockdown of DNA methyltransferase-1 inhibits proliferation and derepresses tumor suppressor genes in myeloma cells. Oncol Lett. 2014 Nov;8(5):2130-2134.
Das DS, Ray A, Das A, Song Y, Tian Z, Oronsky B, Richardson P, Scicinski J, Chauhan D, Anderson KC. A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells. Leukemia. 2016 May 24.
Lin L, Wang P, Liu X, Zhao D, Zhang Y, Hao J, Liang X, Huang X, Lu J, Ge Q. Epigenetic regulation of reelin expression in multiple myeloma. Hematol Oncol. 2016 Jun 1.
Fu HY, Sheng JZ, Sheng SF, Zhou HR. n-MSP detection of p16 gene demethylation and transcription in human multiple myeloma U266 cell line induced by arsenic trioxide. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2007 Feb;15(1):79-85.
Hodge DR, Peng B, Cherry JC, Hurt EM, Fox SD, Kelley JA, Munroe DJ, Farrar WL. Interleukin 6 supports the maintenance of p53 tumor suppressor gene promoter methylation. Cancer Res. 2005 Jun 1;65(11):4673-82.
Copyright (c) 2018 Acta Medica Iranica
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.