High Expression of IKZF2 in Malignant T Cells Promotes Disease Progression in Cutaneous T Cell Lymphoma

Authors

  • Bufang Xu
  • Fengjie Liu
  • Yumei Gao
  • Jingru Sun
  • Yingyi Li
  • Yuchieh Lin
  • Xiangjun Liu
  • Yujie Wen
  • Shengguo Yi
  • Jingyang Dang
  • Ping Tu
  • Yang Wang Department of Dermatology and Venereology, Peking University First Hospital, No.8 Xishiku Street, Xi Cheng District, Beijing 100034, China

DOI:

https://doi.org/10.2340/actadv.v101.570

Keywords:

Cutaneous T cell lymphoma, IKZF2, apoptosis, PD1, IL-10

Abstract

Cutaneous T cell lymphoma is a generally indolent disease derived from skin-homing mature T cells. However, in advanced stages, cutaneous T cell lymphoma may manifest aggressive clinical behaviour and lead to a poor prognosis. The mechanism of disease progression in cutaneous T cell lymphoma remains unknown. This study, based on a large clinical cohort, found that IKZF2, an essential transcription factor during T cell development and differentiation, showed stage- dependent overexpression in the malignant T cells in mycosis fungoides lesions. IKZF2 is specifically over- expressed in advanced-stage mycosis fungoides lesions, and correlates with poor prognosis. Mechanistically, overexpression of IKZF2 promotes cutaneous T cell lymphoma progression via inhibiting malignant cell apoptosis and may contribute to tumour immune escape by downregulating major histocompatibility complex II molecules and up-regulating the production of anti-inflammatory cytokine interleukin-10 by malignant T cells. These results demonstrate the important role of IKZF2 in high-risk cutaneous T cell lymphoma and pave the way for future targeted therapy.

Downloads

Download data is not yet available.

References

Hwang ST, Janik JE, Jaffe ES, Wilson WH. Mycosis fungoides and Sezary syndrome. Lancet (London, England) 2008; 371: 945-957.

https://doi.org/10.1016/S0140-6736(08)60420-1 DOI: https://doi.org/10.1016/S0140-6736(08)60420-1

Rubio Gonzalez B, Zain J, Rosen ST, Querfeld C. Tumor microenvironment in mycosis fungoides and Sezary syndrome. Curr Opin Oncol 2016; 28: 88-96.

https://doi.org/10.1097/CCO.0000000000000243 DOI: https://doi.org/10.1097/CCO.0000000000000243

Wilcox RA. Cutaneous T-cell lymphoma: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol 2017; 92: 1085-1102.

https://doi.org/10.1002/ajh.24876 DOI: https://doi.org/10.1002/ajh.24876

Buus TB, Willerslev-Olsen A, Fredholm S, Blümel E, Nastasi C, Gluud M, et al. Single-cell heterogeneity in Sézary syndrome. Blood Adv 2018; 2: 2115-2126.

https://doi.org/10.1182/bloodadvances.2018022608 DOI: https://doi.org/10.1182/bloodadvances.2018022608

Borcherding N, Voigt AP, Liu V, Link BK, Zhang W, Jabbari A. Single-cell profiling of cutaneous T-cell lymphoma reveals underlying heterogeneity associated with disease progression. Clin Cancer Res 2019; 25: 2996-3005.

https://doi.org/10.1158/1078-0432.CCR-18-3309 DOI: https://doi.org/10.1158/1078-0432.CCR-18-3309

Li Z, Perez-Casellas LA, Savic A, Song C, Dovat S. Ikaros isoforms: the saga continues. World J Biol Chem 2011; 2: 140-145.

https://doi.org/10.4331/wjbc.v2.i6.140 DOI: https://doi.org/10.4331/wjbc.v2.i6.140

Powell MD, Read KA, Sreekumar BK, Oestreich KJ. Ikaros zinc finger transcription factors: regulators of cytokine signaling pathways and CD4(+) T helper cell differentiation. Front Immunol 2019; 10: 1299.

https://doi.org/10.3389/fimmu.2019.01299 DOI: https://doi.org/10.3389/fimmu.2019.01299

Serre K, Benezech C, Desanti G, Bobat S, Toellner KM, Bird R, et al. Helios is associated with CD4 T cells differentiating to T helper 2 and follicular helper T cells in vivo independently of Foxp3 expression. PLoS One 2011; 6: e20731.

https://doi.org/10.1371/journal.pone.0020731 DOI: https://doi.org/10.1371/journal.pone.0020731

Kim HJ, Barnitz RA, Kreslavsky T, Brown FD, Moffett H, Lemieux ME, et al. Stable inhibitory activity of regulatory T cells requires the transcription factor Helios. Science 2015; 350: 334-339.

https://doi.org/10.1126/science.aad0616 DOI: https://doi.org/10.1126/science.aad0616

Jariwala N, Benoit B, Kossenkov AV, Oetjen LK, Whelan TM, Cornejo CM, et al. TIGIT and Helios are highly expressed on CD4(+) T cells in sezary syndrome patients. J Invest Dermatol 2017; 137: 257-260.

https://doi.org/10.1016/j.jid.2016.08.016 DOI: https://doi.org/10.1016/j.jid.2016.08.016

Wysocka M, Kossenkov AV, Benoit BM, Troxel AB, Singer E, Schaffer A, et al. CD164 and FCRL3 are highly expressed on CD4+CD26- T cells in Sézary syndrome patients. J Invest Dermatol 2014; 134: 229-236.

https://doi.org/10.1038/jid.2013.279 DOI: https://doi.org/10.1038/jid.2013.279

Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105: 3768-3785.

https://doi.org/10.1182/blood-2004-09-3502 DOI: https://doi.org/10.1182/blood-2004-09-3502

Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R, et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 2007; 110: 1713-1722.

https://doi.org/10.1182/blood-2007-03-055749 DOI: https://doi.org/10.1182/blood-2007-03-055749

Varghese F, Bukhari AB, Malhotra R, De A. IHC Profiler: an open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples. PLoS One 2014; 9: e96801.

https://doi.org/10.1371/journal.pone.0096801 DOI: https://doi.org/10.1371/journal.pone.0096801

Kong X, Chen J, Xie W, Brown SM, Cai Y, Wu K, et al. Defining UHRF1 domains that support maintenance of human colon cancer DNA methylation and oncogenic properties. Cancer Cell 2019; 35: 633-648e637.

https://doi.org/10.1016/j.ccell.2019.03.003 DOI: https://doi.org/10.1016/j.ccell.2019.03.003

Goepp M, Le Guennec D, Rossary A, Vasson MP. Cell cycle synchronization of the murine EO771 cell line using double thymidine block treatment. Bioessays 2020; 42: e1900116.

https://doi.org/10.1002/bies.201900116 DOI: https://doi.org/10.1002/bies.201900116

Chung S, Kim SH, Seo Y, Kim SK, Lee JY. Quantitative analysis of cell proliferation by a dye dilution assay: application to cell lines and cocultures. Cytometry A 2017; 91: 704-712.

https://doi.org/10.1002/cyto.a.23105 DOI: https://doi.org/10.1002/cyto.a.23105

Lei KF, Kao CH, Tsang NM. High throughput and automatic colony formation assay based on impedance measurement technique. Analyt Bioanalyt Chem 2017; 409: 3271-3277.

https://doi.org/10.1007/s00216-017-0270-5 DOI: https://doi.org/10.1007/s00216-017-0270-5

Liu F, Gao Y, Xu B, Xiong S, Yi S, Sun J, et al. PEG10 amplification at 7q21.3 potentiates large-cell transformation in cutaneous T-cell lymphoma. Blood 2021 Sep 28 (Online ahead of print).

https://doi.org/10.1182/blood.2021012091 DOI: https://doi.org/10.1182/blood.2021012091

Vural S, Akay BN, Botsalı A, Atilla E, Parlak N, Okçu Heper A, et al. Transformation of mycosis fungoides/sezary syndrome: clinical characteristics and prognosis. Turk J Haematol 2018; 35: 35-41.

https://doi.org/10.4274/tjh.2016.0502 DOI: https://doi.org/10.4274/tjh.2016.0502

Vergier B, de Muret A, Beylot-Barry M, Vaillant L, Ekouevi D, Chene G, et al. Transformation of mycosis fungoides: clinicopathological and prognostic features of 45 cases. French Study Group of Cutaneious Lymphomas. Blood 2000; 95: 2212-2218.

Starkebaum G, Loughran TP, Jr., Waters CA, Ruscetti FW. Establishment of an IL-2 independent, human T-cell line possessing only the p70 IL-2 receptor. Int J Cancer 1991; 49: 246-253.

https://doi.org/10.1002/ijc.2910490218 DOI: https://doi.org/10.1002/ijc.2910490218

Gazdar AF, Carney DN, Bunn PA, Russell EK, Jaffe ES, Schechter GP, et al. Mitogen requirements for the in vitro propagation of cutaneous T-cell lymphomas. Blood 1980; 55: 409-417. DOI: https://doi.org/10.1182/blood.V55.3.409.bloodjournal553409

https://doi.org/10.1182/blood.V55.3.409.409 DOI: https://doi.org/10.1182/blood.V55.3.409.409

Thornton AM, Shevach EM. Helios: still behind the clouds. Immunology 2019; 158: 161-170.

https://doi.org/10.1111/imm.13115 DOI: https://doi.org/10.1111/imm.13115

McGirt LY, Degesys CA, Johnson VE, Zic JA, Zwerner JP, Eischen CM. TOX expression and role in CTCL. J Eur Acad Dermatol Venereol 2016; 30: 1497-1502.

https://doi.org/10.1111/jdv.13651 DOI: https://doi.org/10.1111/jdv.13651

Goodlad RA. Quantification of epithelial cell proliferation, cell dynamics, and cell kinetics in vivo. Wiley Interdiscip Rev Develop Biol 2017; 6.

https://doi.org/10.1002/wdev.274 DOI: https://doi.org/10.1002/wdev.274

Alfei F, Kanev K, Hofmann M, Wu M, Ghoneim HE, Roelli P, et al. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 2019; 571: 265-269.

https://doi.org/10.1038/s41586-019-1326-9 DOI: https://doi.org/10.1038/s41586-019-1326-9

Sowell RT, Kaech SM. Probing the diversity of T cell dysfunction in cancer. Cell 2016; 166: 1362-1364.

https://doi.org/10.1016/j.cell.2016.08.058 DOI: https://doi.org/10.1016/j.cell.2016.08.058

Wang L, Ni X, Covington KR, Yang BY, Shiu J, Zhang X, et al. Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes. Nat Genet 2015; 47: 1426-1434.

https://doi.org/10.1038/ng.3444 DOI: https://doi.org/10.1038/ng.3444

Cetinözman F, Jansen PM, Vermeer MH, Willemze R. Differential expression of programmed death-1 (PD-1) in Sézary syndrome and mycosis fungoides. Arch Dermatol 2012; 148: 1379-1385.

https://doi.org/10.1001/archdermatol.2012.2089 DOI: https://doi.org/10.1001/archdermatol.2012.2089

Gao Y, Liu F, Sun J, Wen Y, Tu P, Kadin ME, et al. Differential SATB1 expression reveals heterogeneity of cutaneous T-cell lymphoma. J Invest Dermatol 2021; 141: 607-618.e606.

https://doi.org/10.1016/j.jid.2020.05.120 DOI: https://doi.org/10.1016/j.jid.2020.05.120

Wognum B, Yuan N, Lai B, Miller CL. Colony forming cell assays for human hematopoietic progenitor cells. Methods Mol Biol 2013; 946: 267-283.

https://doi.org/10.1007/978-1-62703-128-8_17 DOI: https://doi.org/10.1007/978-1-62703-128-8_17

Quah BJ, Parish CR. The use of carboxyfluorescein diacetate succinimidyl ester (CFSE) to monitor lymphocyte proliferation. J Vis Exp 2010; 44: 2259.

https://doi.org/10.3791/2259 DOI: https://doi.org/10.3791/2259

Sahin M, Sahin E. Prostaglandin E2 reverses the effects of DNA methyltransferase inhibitor and TGFB1 on the conversion of naive t cells to iTregs. Transfus Med Hemother 2020; 47: 244-253.

https://doi.org/10.1159/000502582 DOI: https://doi.org/10.1159/000502582

Salvador-Martín S, Kaczmarczyk B, Álvarez R, Navas-López VM, Gallego-Fernández C, Moreno-Álvarez A, et al. Whole transcription profile of responders to anti-TNF drugs in pediatric inflammatory bowel disease. Pharmaceutics 2021; 13: 77.

https://doi.org/10.3390/pharmaceutics13010077 DOI: https://doi.org/10.3390/pharmaceutics13010077

Vella D, Marini S, Vitali F, Di Silvestre D, Mauri G, Bellazzi R. MTGO: PPI network analysis via topological and functional module identification. Sci Rep 2018; 8: 5499.

https://doi.org/10.1038/s41598-018-23672-0 DOI: https://doi.org/10.1038/s41598-018-23672-0

Irizarry RA, Wang C, Zhou Y, Speed TP. Gene set enrichment analysis made simple. Stat Methods Med Res 2009; 18: 565-575.

https://doi.org/10.1177/0962280209351908 DOI: https://doi.org/10.1177/0962280209351908

Delgado M, Tesfaigzi Y. BH3-only proteins, Bmf and Bim, in autophagy. Cell Cycle 2013; 12: 3453-3454.

https://doi.org/10.4161/cc.26696 DOI: https://doi.org/10.4161/cc.26696

An Q, Zhou Y, Han C, Zhou Y, Li F, Li D. BTG3 overexpression suppresses the proliferation and invasion in epithelial ovarian cancer cell by regulating AKT/GSK3beta/beta-catenin signaling. Reprod Sci 2017; 24: 1462-1468.

https://doi.org/10.1177/1933719117691143 DOI: https://doi.org/10.1177/1933719117691143

Lv C, Wang H, Tong Y, Yin H, Wang D, Yan Z, et al. The function of BTG3 in colorectal cancer cells and its possible signaling pathway. J Cancer Res Clin Oncol 2018; 144: 295-308.

https://doi.org/10.1007/s00432-017-2561-9 DOI: https://doi.org/10.1007/s00432-017-2561-9

Broers JL, Ramaekers FC. The role of the nuclear lamina in cancer and apoptosis. Adv Exp Med Biol 2014; 773: 27-48.

https://doi.org/10.1007/978-1-4899-8032-8_2 DOI: https://doi.org/10.1007/978-1-4899-8032-8_2

Al-Matouq J, Holmes TR, Hansen LA. CDC25B and CDC25C overexpression in nonmelanoma skin cancer suppresses cell death. Mol Carcinog 2019; 58: 1691-1700.

https://doi.org/10.1002/mc.23075 DOI: https://doi.org/10.1002/mc.23075

Tran AN, Walker K, Harrison DG, Chen W, Mobley J, Hocevar L, et al. Reactive species balance via GTP cyclohydrolase I regulates glioblastoma growth and tumor initiating cell maintenance. Neuro Oncol 2018; 20: 1055-1067.

https://doi.org/10.1093/neuonc/noy012 DOI: https://doi.org/10.1093/neuonc/noy012

Gao Y, Wang W, Cao J, Wang F, Geng Y, Cao J, et al. Upregulation of AUF1 is involved in the proliferation of esophageal squamous cell carcinoma through GCH1. Int J Oncol 2016; 49: 2001-2010.

https://doi.org/10.3892/ijo.2016.3713 DOI: https://doi.org/10.3892/ijo.2016.3713

Axelrod ML, Cook RS, Johnson DB, Balko JM. Biological consequences of MHC-II expression by tumor cells in cancer. Clin Cancer Res 2019; 25: 2392-2402.

https://doi.org/10.1158/1078-0432.CCR-18-3200 DOI: https://doi.org/10.1158/1078-0432.CCR-18-3200

Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002; 23: 549-555.

https://doi.org/10.1016/S1471-4906(02)02302-5 DOI: https://doi.org/10.1016/S1471-4906(02)02302-5

Saraiva M, O'Garra A. The regulation of IL-10 production by immune cells. Nat Rev Immunol 2010; 10: 170-181.

https://doi.org/10.1038/nri2711 DOI: https://doi.org/10.1038/nri2711

Mannino MH, Zhu Z, Xiao H, Bai Q, Wakefield MR, Fang Y. The paradoxical role of IL-10 in immunity and cancer. Cancer Lett 2015; 367: 103-107.

https://doi.org/10.1016/j.canlet.2015.07.009 DOI: https://doi.org/10.1016/j.canlet.2015.07.009

Wu X, Hsu DK, Wang KH, Huang Y, Mendoza L, Zhou Y, et al. IL-10 is overexpressed in human cutaneous T-cell lymphoma and is required for maximal tumor growth in a mouse model. Leuk Lymphoma 2019; 60: 1244-1252.

https://doi.org/10.1080/10428194.2018.1516037 DOI: https://doi.org/10.1080/10428194.2018.1516037

Nakase K, Ishimaru F, Fujii K, Tabayashi T, Kozuka T, Sezaki N, et al. Overexpression of novel short isoforms of Helios in a patient with T-cell acute lymphoblastic leukemia. Exp Hematol 2002; 30: 313-317.

https://doi.org/10.1016/S0301-472X(01)00796-2 DOI: https://doi.org/10.1016/S0301-472X(01)00796-2

Asanuma S, Yamagishi M, Kawanami K, Nakano K, Sato-Otsubo A, Muto S, et al. Adult T-cell leukemia cells are characterized by abnormalities of Helios expression that promote T cell growth. Cancer Sci 2013; 104: 1097-1106.

https://doi.org/10.1111/cas.12181 DOI: https://doi.org/10.1111/cas.12181

Park SM, Cho H, Thornton AM, Barlowe TS, Chou T, Chhangawala S, et al. IKZF2 drives leukemia stem cell self-renewal and inhibits myeloid differentiation. Cell Stem Cell 2019; 24: 153-165e157.

https://doi.org/10.1016/j.stem.2018.10.016 DOI: https://doi.org/10.1016/j.stem.2018.10.016

Dovat S, Montecino-Rodriguez E, Schuman V, Teitell MA, Dorshkind K, Smale ST. Transgenic expression of Helios in B lineage cells alters B cell properties and promotes lymphomagenesis. J Immunol 2005; 175: 3508-3515.

https://doi.org/10.4049/jimmunol.175.6.3508 DOI: https://doi.org/10.4049/jimmunol.175.6.3508

Heid JB, Schmidt A, Oberle N, Goerdt S, Krammer PH, Suri-Payer E, et al. FOXP3+CD25- tumor cells with regulatory function in Sezary syndrome. J Invest Dermatol 2009; 129: 2875-2885.

https://doi.org/10.1038/jid.2009.175 DOI: https://doi.org/10.1038/jid.2009.175

Krejsgaard T, Gjerdrum LM, Ralfkiaer E, Lauenborg B, Eriksen KW, Mathiesen AM, et al. Malignant Tregs express low molecular splice forms of FOXP3 in Sezary syndrome. Leukemia 2008; 22: 2230-2239.

https://doi.org/10.1038/leu.2008.224 DOI: https://doi.org/10.1038/leu.2008.224

Litvinov IV, Tetzlaff MT, Thibault P, Gangar P, Moreau L, Watters AK, et al. Gene expression analysis in cutaneous T-cell lymphomas (CTCL) highlights disease heterogeneity and potential diagnostic and prognostic indicators. Oncoimmunology 2017; 6: e1306618.

https://doi.org/10.1080/2162402X.2017.1306618 DOI: https://doi.org/10.1080/2162402X.2017.1306618

Wartewig T, Kurgyis Z, Keppler S, Pechloff K, Hameister E, Ollinger R, et al. PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. Nature 2017; 552: 121-125.

https://doi.org/10.1038/nature24649 DOI: https://doi.org/10.1038/nature24649

Wartewig T, Ruland J. PD-1 tumor suppressor signaling in T cell lymphomas. Trends Immunol 2019; 40: 403-414.

https://doi.org/10.1016/j.it.2019.03.005 DOI: https://doi.org/10.1016/j.it.2019.03.005

Rimsza LM, Roberts RA, Miller TP, Unger JM, LeBlanc M, Braziel RM, et al. Loss of MHC class II gene and protein expression in diffuse large B-cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: a follow-up study from the Leukemia and Lymphoma Molecular Profiling Project. Blood 2004; 103: 4251-4258.

https://doi.org/10.1182/blood-2003-07-2365 DOI: https://doi.org/10.1182/blood-2003-07-2365

Wu X, Schulte BC, Zhou Y, Haribhai D, Mackinnon AC, Plaza JA, et al. Depletion of M2-like tumor-associated macrophages delays cutaneous T-cell lymphoma development in vivo. J Invest Dermatol 2014; 134: 2814-2822.

https://doi.org/10.1038/jid.2014.206 DOI: https://doi.org/10.1038/jid.2014.206

Krejsgaard T, Willerslev-Olsen A, Lindahl LM, Bonefeld CM, Koralov SB, Geisler C, et al. Staphylococcal enterotoxins stimulate lymphoma-associated immune dysregulation. Blood 2014; 124: 761-770.

https://doi.org/10.1182/blood-2014-01-551184 DOI: https://doi.org/10.1182/blood-2014-01-551184

Sridharan R, Smale ST. Predominant interaction of both Ikaros and Helios with the NuRD complex in immature thymocytes. J Biol Chem 2007; 282: 30227-30238.

https://doi.org/10.1074/jbc.M702541200 DOI: https://doi.org/10.1074/jbc.M702541200

Heizmann B, Kastner P, Chan S. The Ikaros family in lymphocyte development. Curr Opin Immunol 2018; 51: 14-23.

https://doi.org/10.1016/j.coi.2017.11.005 DOI: https://doi.org/10.1016/j.coi.2017.11.005

Published

2021-12-07

How to Cite

Xu, B., Liu, F., Gao, Y., Sun, J., Li, Y., Lin, Y., Liu, X., Wen, Y., Yi, S., Dang, J., Tu, P., & Wang, Y. (2021). High Expression of IKZF2 in Malignant T Cells Promotes Disease Progression in Cutaneous T Cell Lymphoma. Acta Dermato-Venereologica, 101(12), adv00613. https://doi.org/10.2340/actadv.v101.570