Abstract
Normal human CD4+ T-lymphocytes can undergo malignant transformation during prolong cultivation in conditions of high endonuclease G (EndoG) expression or after DNA damage. The aim of this work was to study biochemical and cytogenetic features of transformed ex vivo human malignant CD4+ T- lymphocytes, as well as biochemical and morphological characteristics of tumors that develop in athymic mice after transplantation of these cells. The telomerase activity was higher and telomere length was shorter in tumor cells than in control cells. Transformed malignant cells exhibited a high level of chromosomal aberrations. Expression of genes regulating the cell cycle changed in transformed malignant CD4+ T-lymphocytes and tumor cells. The tumors that developed were classified as multicomponent Т-cell lymphomas and panniculitis-like T-cell lymphomas. Thus, transformed CD4+ T-lymphocytes can generate malignant tumors of various histogenesis.
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REFERENCES
Balmus, G., Lim, P.X., Oswald, A., Hume, K.R., Cassano, A., Pierre, J., Hill, A., Huang, W., August, A., Stokol, T., Southard, T., and Weiss, R.S., HUS1 regulates in vivo responses to genotoxic chemotherapies, Oncogene, 2016, vol. 35, pp. 662–669.
Blackburn, E.H., Telomeres and telomerase: their mechanisms of action and the effects of altering their functions, FEBS Lett., 2005, vol. 579, pp. 859–862.
Campisi, J., Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors, Cell, 2005, vol. 120, pp. 513–522.
Campisi, J., Aging, cellular senescence, and cancer, Annu. Rev. Physiol., 2013, vol. 75, pp. 685–705.
Cawthon, R.M., Telomere measurement by quantitative PCR, Nucleic Acids Res, 2002, vol. 30. e47.
Chen, J.-H., Hales, C.N., and Ozanne, S.E., DNA damage, cellular senescence and organismal ageing: causal or correlative?, Nucleic Acids Res., 2007, vol. 35, pp. 7417–7428.
d’Adda di Fagagna, F., Living on a break: cellular senescence as a DNA-damage response, Nat. Rev. Cancer, 2008, vol. 8, pp. 512–522.
DeVore, G.R., The genetic sonogram: its use in the detection of chromosomal abnormalities in fetuses of women of advanced maternal age, Prenat. Diagn., 2001, vol. 21, pp. 40–55.
Dimri, G.P., What has senescence got to do with cancer?, Cancer Cell, 2005, vol. 7, pp. 505–12.
Hanahan, D. and Weinberg, R.A., The hallmarks of cancer, Cell, 2000, vol. 100, pp. 57–70.
Hiyama, E. and Hiyama, K., Telomerase detection in the diagnosis and prognosis of cancer, Cytotechnology, 2004, vol. 45, pp. 61–74.
ISCN, International Standing Committee on Human Cytogenetic Nomenclature, Shaffer, L.G., McGowan-Jordan, J., and Schmid, M., Eds., Karger, 2013.
Jiang, Q., Xu, Y., Li, X., Peng, Q., Cai, H., and Wang, J., Progressive and painful wound as a feature of subcutaneous panniculitis-like T-cell lymphoma (SPTCL): report of a case and review of literature, Int. J. Clin. Exp. Pathol., 2015, vol. 8, pp. 735–742.
Kim, N.W., Piatyszek, M.A., Prowse, K.R., Harley, C.B., West, M.D., Ho, P.L., Coviello, G.M., Wright, W.E., Weinrich, S.L., and Shay, J.W., Specific association of human telomerase activity with immortal cells and cancer, Science, 1994, vol. 266, pp. 2011–2015.
Kryston, T.B., Georgiev, A.B., Pissis, P., and Georgakilas, A.G., Role of Oxidative Stress and DNA Damage in Human Carcinogenesis, Mutat. Res. Mol. Mech. Mutagen., 2011, vol. 711, pp. 193–201.
Metsalu, T., and Vilo, J., ClustVis: a web tool for visualizing clustering of multivariate data using principal component analysis and heatmap, Nucleic Acids Res., 2015, vol. 43, pp. W566–W570.
Meyerson, M., Counter, C.M., Eaton, E, .N., Ellisen, L.W., Steiner, P., Caddle, S.D., Ziaugra, L., Beijersbergen, R.L., Davidoff, M.J., Liu, Q., Bacchetti, S., Haber, D.A., and Weinberg, R.A., HEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization, Cell, 1997, vol. 90, pp. 785–795.
Mikhailov, V.M., Kaminskaya, E.V., Popov, B.V., Kuzovatov, S.N., Skripkina, N.S., Kosyakova, G.P., Zaichik, A.M., Grinchuk, T.M., and Nikolsky, N.N., Characteristics of tumors developed in mdx mice after transplantation of GFP-positive mesenchymal stem cells isolated from bone marrow of transgenic C57BL/6 mice, Cell Tissue Biol., 2010, vol. 4, pp. 419–423.
Miura, M., Miura, Y., Padilla-Nash, H.M., Molinolo, A.A., Fu, B., Patel, V., Seo, B.-M., Sonoyama, W., Zheng, J.J., Baker, C, C., Chen, W., Ried, T., and Shi, S., Accumulated chromosomal instability in murine bone marrow mesenchymal stem cells leads to malignant transformation, Stem Cells, 2006, vol. 24, pp. 1095–1103.
Moskaleva, E.Y., Zhorova, E.S., Semochkina, Yu.P., Rodina, A.V., Vysotskaya, O.V., Glukhov, A.I., Chukalova, A.A., Posypanova, G.A., and Saprykin, V.P., Characteristics of tumors that have developed in mice injected with syngenic irradiated mesenchymal stem cells of bone marrow, Cell Tissue Biol., 2017, vol. 11, pp. 381–388.
Pelegrini, A.L., Moura, D.J., Brenner, B.L., Ledur, P.F., Maques, G.P., Henriques, J.A.P., Saffi, J., and Lenz, G., Nek1 silencing slows down DNA repair and blocks DNA damage-induced cell cycle arrest, Mutagenesis, 2010, vol. 25, pp. 447–454.
Popov, B.V., Petrov, N.S., Mikhailov, V.M., Tomilin, A.N., Alekseenko, L.L., Grinchuk, T.M., and Zaichik, A.M., Spontaneous transformation and immortalization of mesenchymal stem cells in vitro, Cell Tissue Biol., 2009, vol. 3, pp. 110–120.
Reissig, K., Silver, A., Hartig, R., Schinlauer, A., Walluscheck, D., Guenther, T., Siedentopf, S., Ross, J., Vo, D.-K., Roessner, A., and Poehlmann-Nitsche, A., Chk1 promotes DNA damage response bypass following oxidative stress in a model of hydrogen peroxide-associated ulcerative colitis through JNK inactivation and chromatin binding, Oxid. Med. Cell. Longev., 2017, pp. 1–20. https://doi.org/10.1155/2017/9303158
Rodriguez, R., Rubio, R., and Menendez, P., Modeling sarcomagenesis using multipotent mesenchymal stem cells, Cell Res., 2012, vol. 22, pp. 62–77. https://doi.org/10.1038/cr.2011.157
Saebøe-Larssen, S., Fossberg, E., and Gaudernack, G., Characterization of novel alternative splicing sites in human telomerase reverse transcriptase (hTERT): analysis of expression and mutual correlation in mRNA isoforms from normal and tumour tissues, BMC Mol. Biol., 2006, vol. 7, p. 26. https://doi.org/10.1186/1471-2199-7-26
Satyanarayana, A. and Kaldis, P., Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms, Oncogene, 2009, vol. 28, pp. 2925–2939.
Solomon, E., Borrow, J., and Goddard, A.D., Chromosome aberrations and cancer, Science, 1991, vol. 254, pp. 1153–1160.
Sugeeth, M.T., Narayanan, G., Jayasudha, A.V., and Nair, R.A., Subcutaneous panniculitis-like T-cell lymphoma, Proc. (Bayl. Univ. Med. Cent.), 2017, vol. 30, pp. 76–77.
Sun, X., and Kaufman, P.D., Ki-67: more than a proliferation marker, Chromosoma, 2018, vol. 127, pp. 175–186. https://doi.org/10.1007/s00412-018-0659-8
Todd, D.E., Densham, R.M., Molton, S.A., Balmanno, K., Newson, C., Weston, C.R., Garner, A.P., Scott, L., and Cook, S.J., ERK1/2 and p38 cooperate to induce a P21CIP1-dependent G1 cell cycle arrest, Oncogene, 2004, vol. 23, pp. 3284–3295.
Ulaner, G.A., Hu, J.F., Vu, T.H., Giudice, L.C., and Hoffman, A.R., Telomerase activity in human development is regulated by human telomerase reverse transcriptase (hTERT) transcription and by alternate splicing of hTERT transcripts, Cancer Res., 1998, vol. 58, pp. 4168–4172.
Vasina, D.A., Zhdanov, D.D., Orlova, E.V., Orlova, V.S., Pokrovskaya, M.V., Aleksandrova, S.S., and Sokolov, N.N., Apoptotic endonuclease EndoG inhibits telomerase activity and induces malignant transformation of human CD4+ T cells, Biochemistry (Moscow), 2017, vol. 82, pp. 24–37.
Vineis, P., Schatzkin, A., and Potter, J.D., Models of carcinogenesis: an overview, Carcinogenesis, 2010, vol. 31, pp. 1703–1709.
Vorsanova, S.G., Iourov, I.Y., Kolotii, A.D., Beresheva, A.K., Demidova, I.A., Kurinnaya, O.S., Kravets, V.S., Monakhov, V.V., Soloviev, I.V., and Yurov, Y.B., Chromosomal mosaicism in spontaneous abortions: analysis of 650 cases, Russ. J. Genet., 2010, vol. 46, pp. 1197–1200.
Ye, J., Huang, X., Hsueh, E.C., Zhang, Q., Ma, C., Zhang, Y., Varvares, M.A., Hoft, D.F., and Peng, G., Human regulatory T cells induce T-lymphocyte senescence, Blood, 2012, vol. 120, pp. 2021–2031.
Zhdanov, D.D., Pokrovsky, V.S., Pokrovskaya, M.V., Alexandrova, S.S., Eldarov, M.A., Grishin, D.V., Basharov, M.M., Gladilina, Y.A., Podobed, O.V., and Sokolov, N.N., Rhodospirillum rubrum L-asparaginase targets tumor growth by a dual mechanism involving telomerase inhibition, Biochem. Biophys. Res. Commun., 2017a, vol. 492, pp. 282–288. https://doi.org/10.1016/j.bbrc.2017.08.078
Zhdanov, D.D., Vasina, D.A., Grachev, V.A., Orlova, E.V., Orlova, V.S., Pokrovskaya, M.V., Alexandrova, S.S., and Sokolov, N.N., Alternative splicing of telomerase catalytic subunit hTERT generated by apoptotic endonuclease EndoG induces human CD4+ T cell death, Eur. J. Cell Biol., 2017b, vol. 96, pp. 653–664.
Zhdanov, D.D., Vasina, D.A., Orlova, E.V., Orlova, V.S., Pokrovskaya, M.V., Aleksandrova, S.S., and Sokolov, N.N., Apoptotic endonuclease EndoG regulates alternative splicing of human telomerase catalytic subunit hTERT, Biochemistry (Moscow), Suppl. Ser. B Biomed. Chem., 2017c, vol. 11, pp. 154–165.
Zhdanov, D.D., Vasina, D.A., Orlova, E.V., Orlova, V.S., Pokrovsky, V.S., Pokrovskaya, M.V., Aleksandrova, S.S., and Sokolov, N.N., Cisplatin-induced apoptotic endonuclease EndoG inhibits telomerase activity and causes malignant transformation of human CD4+ T lymphocytes, Biochemistry (Moscow). Suppl. Ser. B. Biomed. Chem., 2017d, vol. 11, pp. 251–264.
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Translated by I. Fridlyanskaya
Abbreviations: AS—alternative splicing, hTERT—human telomerase reverse transcriptase, TRAP—telomeric repeat amplification protocol.
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Zhdanov, D.D., Gabasvili, A.N., Gladilina, Y.A. et al. Characteristics of Tumors That Develop in Athymic Mice after Transplantation of Human Malignant CD4+ T-lymphocytes Transformed ex vivo. Cell Tiss. Biol. 13, 176–187 (2019). https://doi.org/10.1134/S1990519X19030118
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DOI: https://doi.org/10.1134/S1990519X19030118