Abstract
Severe aplastic anemia (SAA) is a rare autoimmune disease characterized by severe pancytopenia and bone marrow failure, which is caused by activated T lymphocytes. In the present study, we evaluated histone H3 acetylation levels of bone marrow CD8+ T cells in SAA patients, and analyzed its correlation with clinical condition parameters. We found that the percentages of CD8+ T cell histone H3 acetylation in patients with untreated SAA, recovering SAA (R-SAA) and normal control, were 1.21 ± 0.08, 1.05 ± 0.36, and 1.00 ± 0.41, respectively, with no significant statistical differences. However, the amount of CD8+ T cell histone H3 acetylation from untreated SAA was 176.21 ± 32.22 μg/mg protein, which was significantly higher than that of complete response (CR)-SAA (104.29 ± 62.06 μg/mg protein) and normal control (133.94 ± 56.27 μg/mg protein) (P < 0.05) groups. Moreover, histone H3 acetylation amount of CD8+ T cell was significantly and negatively correlated with absolute neutrophil count, proportion of reticulocytes, ratio of CD4+ to CD8+ T cell in peripheral blood, and percentage of bone marrow erythroid (P < 0.05). To some extent, it also negatively correlated with hemoglobin level, platelet count, percentage of bone marrow granulocyte, and megakaryocyte count. Abnormal histone H3 acetylation of CD8+ T cells may thus play a role in the immune pathogenesis of SAA.
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References
Young NS, Scheinberg P, Calado RT. Aplastic anemia. Curr Opin Hematol. 2008;15:162–8.
Marsh JC, Ball SE, Cavenagh J, Darbyshire P, Dokal I, Gordon-Smith EC, et al. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol. 2009;147:43–70.
Zheng M, Liu C, Fu R, Wang H, Wu Y, Li L, et al. Abnormal immunomodulatory ability on memory T cells in humans with severe aplastic anemia. Int J Clin Exp Pathol. 2015;8:3659–69.
Xing L, Liu C, Fu R, Wang H, Wang J, Liu X, et al. CD8+ HLA-DR+ T cells are increased in patients with severe aplastic anemia. Mol Med Rep. 2014;10:1252–8.
Inche AG, La Thangue NB. Chromatin control and cancer-drug discovery: realizing the promise. Drug Discov Today. 2006;11:97–109.
Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004;429:457–63.
Nightingale KP, O’Neill LP, Turner BM. Histone modifications: signalling receptors and potential elements of a heritable epigenetic code. Curr Opin Genet Dev. 2006;16:125–36.
Yun M, Wu J, Workman JL, Li B. Readers of histone modifications. Cell Res. 2011;21:564–78.
Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21:381–95.
Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 2006;5:769–84.
Kroesen M, Gielen P, Brok IC, Armandari I, Hoogerbrugge PM, Adema GJ. HDAC inhibitors and immunotherapy; a double edged sword? Oncotarget. 2014;5:6558–72.
Thiagalingam S, Cheng KH, Lee HJ, Mineva N, Thiagalingam A, Ponte JF. Histone deacetylases: unique players in shaping the epigenetic histone code. Ann N Y Acad Sci. 2003;983:84–100.
Roth SY, Denu JM, Allis CD. Histone acetyltransferases. Ann Rev Biochem. 2001;70:81–120.
de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 2003;370:737–49.
Camitta BM, Thomas ED, Nathan DG, Santos G, Gordon-Smith EC, Gale RP, et al. Severe aplastic anemia: a prospective study of the effect of early marrow transplantation on acute mortality. Blood. 1976;48:63–70.
Bacigalupo A, Hows J, Gluckman E, Nissen C, Marsh J, Van Lint MT, et al. Bone marrow transplantation (BMT) versus immunosuppression for the treatment of severe aplastic anaemia (SAA): a report of the EBMT SAA working party. Br J Haematol. 1988;70:177–82.
Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet. 2005;37:391–400.
Moreno DA, Scrideli CA, Cortez MA, de Paula Queiroz R, Valera ET, da Silva Silveira V, et al. Differential expression of HDAC3, HDAC7 and HDAC9 is associated with prognosis and survival in childhood acute lymphoblastic leukaemia. Br J Haematol. 2010;150:665–73.
Van Damme M, Crompot E, Meuleman N, Mineur P, Bron D, Lagneaux L, et al. HDAC isoenzyme expression is deregulated in chronic lymphocytic leukemia B-cells and has a complex prognostic significance. Epigenetics. 2012;7:1403–12.
Adams H, Fritzsche FR, Dirnhofer S, Kristiansen G, Tzankov A. Class I histone deacetylases 1, 2 and 3 are highly expressed in classical Hodgkin’s lymphoma. Expert Opin Ther Targets. 2010;14:577–84.
Wang JC, Kafeel MI, Avezbakiyev B, Chen C, Sun Y, Rathnasabapathy C, et al. Histone deacetylase in chronic lymphocytic leukemia. Oncology. 2011;81:325–9.
Leggatt GR, Gabrielli B. Histone deacetylase inhibitors in the generation of the anti-tumour immune response. Immunol Cell Biol. 2012;90:33–8.
Noro R, Miyanaga A, Minegishi Y, Okano T, Seike M, Soeno C, et al. Histone deacetylase inhibitor enhances sensitivity of non-small-cell lung cancer cells to 5-FU/S-1 via down-regulation of thymidylate synthase expression and up-regulation of p21(waf1/cip1) expression. Cancer Sci. 2010;101:1424–30.
Miao F, Smith DD, Zhang L, Min A, Feng W, Natarajan R. Lymphocytes from patients with type 1 diabetes display a distinct profile of chromatin histone H3 lysine 9 dimethylation: an epigenetic study in diabetes. Diabetes. 2008;57:3189–98.
Hewagama A, Richardson B. The genetics and epigenetics of autoimmune diseases. J Autoimmun. 2009;33:3–11.
Hu N, Qiu X, Luo Y, Yuan J, Li Y, Lei W, et al. Abnormal histone modification patterns in lupus CD4+ T cells. J Rheumatol. 2008;35:804–10.
Glozak MA, Sengupta N, Zhang X, Seto E. Acetylation and deacetylation of non-histone proteins. Gene. 2005;363:15–23.
Fernández-Sánchez A, Baragaño Raneros A, Carvajal Palao R, Sanz AB, Ortiz A, Ortega F, et al. DNA demethylation and histone H3K9 acetylation determine the active transcription of the NKG2D gene in human CD8+ T and NK cells. Epigenetics. 2013;8:66–78.
Araki Y, Fann M, Wersto R, Weng NP. Histone acetylation facilitates rapid and robust memory CD8 T cell response through differential expression of effector molecules (eomesodermin and its targets: perforin and granzyme B). J Immunol. 2008;180:8102–8.
Chandele A, Joshi NS, Zhu J, Paul WE, Leonard WJ, Kaech SM. Formation of IL-7Rαhigh and IL-7Rαlow CD8 T cells during infection is regulated by the opposing functions of GABPα and Gfi-1. J Immunol. 2008;180:5309–19.
Zonghong S, Meifeng T, Huaquan W, Limin X, Jun W, Rong F, et al. Circulating myeloid dendritic cells are increased in individuals with severe aplastic anemia. Int J Hematol. 2011;93:156–62.
Wang X, Hayes JJ. Acetylation mimics within individual core histone tail domains indicate distinct roles in regulating the stability of higher-order chromatin structure. Mol Cell Biol. 2008;28:227–36.
Tschismarov R, Firner S, Gil-Cruz C, Göschl L, Boucheron N, Steiner G, et al. HDAC1 controls CD8+ T cell homeostasis and antiviral response. PLoS One. 2014;9:e110576.
Acknowledgments
This work was supported by grants from the National Natural Science Foundation of China (81170472; 81370607; and 81400085), Tianjin Medical University General Hospital funding (303070401301), Tianjin Municipal Natural Science Foundation (12JCZDJC21500), Tianjin Cancer Research of Major Projects (12ZCDZSY17900 and 12ZCDZSY18000), and Tianjin Science and Technology Support Key Projects (20140109).
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W. Qi, Li Yan, and C. Liu contributed equally to this work.
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Qi, W., Yan, L., Liu, C. et al. Abnormal histone acetylation of CD8+ T cells in patients with severe aplastic anemia. Int J Hematol 104, 540–547 (2016). https://doi.org/10.1007/s12185-016-2061-8
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DOI: https://doi.org/10.1007/s12185-016-2061-8