Abstract
Cutaneous T-cell lymphoma is a heterogeneous group of non-Hodgkin’s lymphoma, characterized by an infiltration of malignant T cells in the skin. The most common subgroups include mycosis fungoides followed by the aggressive leukaemic variant, Sézary syndrome. The pathophysiology of this neoplasm is poorly understood. The diagnosis of mycosis fungoides at the early stages can be challenging due to phenotypic similarities with other skin conditions. A lack of understanding of the aetiopathology of this neoplasia makes prognosis and diagnosis, as well as the development of targeted therapies aimed at long remission, challenging. This review provides an update on the aetiopathology of cutaneous T-cell lymphoma with regards to genetic and epigenetic alterations, current diagnostic tools and treatments, as well as emerging therapies.
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References
Bagherani N, Smoller BR. An overview of cutaneous T cell lymphomas. F1000Research 2016; 5: 1882.
Chung CG, Poligone B. Cutaneous T cell Lymphoma: an update on pathogenesis and systemic therapy. Curr Hematol Malig Rep 2015; 10: 468–76.
Dulmage BO, Kong BY, Holzem K, Guitart J. What is new in CTCL-pathogenesis, diagnosis, and treatments. Curr Dermatol Rep 2018; 7: 91–8.
Jawed SI, Myskowski PL, Horwitz S, Moskowitz A, Querfeld C. Primary cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome). J Am Acad Dermatol 2014; 70: 205.e1–16.
Gjerdrum LM, Woetmann A, Odum N, et al. FOXP3+ regulatory T cells in cutaneous T-cell lymphomas: association with disease stage and survival. Leukemia 2007; 21: 2512–8.
van Doorn R, Zoutman WH, Dijkman R, et al. Epigenetic profiling of cutaneous T-cell lymphoma: promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73. J Clin Oncol 2005; 23: 3886–96.
Stadler R, Stranzenbach R. Molecular pathogenesis of cutaneous lymphomas. Exp Dermatol 2018; 27: 1078–83.
Kim EJ, Hess S, Richardson SK, et al. Immunopathogenesis and therapy of cutaneous T cell lymphoma. J Clin Invest 2005; 115: 798–812.
Wong HK, Wilson AJ, Gibson HM, et al. Increased expression of CTLA-4 in malignant T cells from patients with mycosis fungoides — cutaneous T-cell lymphoma. J Invest Dermatol 2006; 126: 212–9.
Abraham RM, Zhang Q, Odum N, Wasik MA. The role of cytokine signaling in the pathogenesis of cutaneous T-cell lymphoma. Cancer Biol Ther 2011; 12: 1019–22.
Wilcox RA. Cutaneous T-cell lymphoma: 2014 Update on diagnosis, risk-stratification, and management. Am J Hematol 2014; 89: 837–51.
Ormsby A, Bergfeld WF, Tubbs RR, Hsi DE. Evaluation of a new paraffin-reactive CD7 T-cell deletion marker and a polymerase chain reaction-based T-cell receptor gene rearrangement assay: implications for diagnosis of mycosis fungoides in community clinical practice. J Am Acad Dermatol 2001; 45: 405–13.
Hristov AC, Vonderheid EC, Borowitz MJ. Simplified flow cytometric assessment in Mycosis fungoides and Sézary syndrome. Am J Clin Pathol 2011; 136: 944–53.
Boonk SE, Zoutman WH, Marie-Cardine A, et al. Evaluation of immunophenotypic and molecular biomarkers for Sézary syndrome using standard operating procedures: a multicenter study of 59 patients. J Invest Dermatol 2016; 136: 1364–72.
Klemke CD, Booken N, Weiss C, et al. Histopathological and immunophenotypical criteria for the diagnosis of Sézary syndrome in differentiation from other erythrodermic skin diseases: a European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force Study of 97 cases. Br J Dermatol 2015; 173: 93–105.
Yawalkar N, Ferenczi K, Jones DA, et al. Profound loss of T-cell receptor repertoire complexity in cutaneous T-cell lymphoma. Blood 2003; 102: 4059–66.
Kirsch IR, Watanabe R, O’Malley JT, et al. TCR sequencing facilitates diagnosis and identifies mature T cells as the cell of origin in CTCL. Sci Transl Med 2015; 7: 308ra158.
Beylot-Barry M, Sibaud V, Thiebaut R, et al. Evidence that an identical T cell clone in skin and peripheral blood lymphocytes is an independent prognostic factor in primary cutaneous Tcell lymphomas. J Invest Dermatol 2001; 117: 920–6.
Wilcox RA. Cutaneous T-cell lymphoma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol 2016; 91: 151–65.
Thurber SE, Zhang B, Kim YH, Schrijver I, Zehnder J, Kohler S. T-cell clonality analysis in biopsy specimens from two different skin sites shows high specificity in the diagnosis of patients with suggested mycosis fungoides. J Am Acad Dermatol 2007; 57: 782–90.
Thurber SE, Zhang B, Kim YH, Schrijver I, Zehnder J, Kohler S. T-cell clonality analysis in biopsy specimens from two different skin sites shows high specificity in the diagnosis of patients with suggested mycosis fungoides. J Am Acad Dermatol 2007; 57: 782–90.
Ponti R, Quaglino P, Novelli M, et al. T-cell receptor gamma gene rearrangement by multiplex polymerase chain reaction/heteroduplex analysis in patients with cutaneous T-cell lymphoma (mycosis fungoides/Sézary syndrome) and benign inflammatory disease: correlation with clinical, histological and immunophenotypical findings. Br J Dermatol 2005; 153: 565–73.
Massone C, Crisman G, Kerl H, Cerroni L. The prognosis of early mycosis fungoides is not influenced by phenotype and T-cell clonality. Br J Dermatol 2008; 159: 881–6.
Agar NS, Wedgeworth E, Crichton S, et al. Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol 2010; 28: 4730–9.
Epling-Burnette PK, Painter JS, Rollison DE, et al. Prevalence and clinical association of clonal T-cell expansions in myelodysplastic syndrome. Leukemia 2007; 21: 659–67.
Kohler S, Jones CD, Warnke RA, Zehnder JL. PCR-heteroduplex analysis of T-cell receptor gamma gene rearrangement in paraffin-embedded skin biopsies. Am J Dermatopathol 2000; 22: 321–7.
Guitart J, Magro C. Cutaneous T-cell lymphoid dyscrasia. Arch Dermatol 2007; 143: 921–32.
Posnett DN, Sinha R, Kabak S, Russo C. Clonal populations of T cells in normal elderly humans: the T cell equivalent to “benign monoclonal gammapathy”. J Exp Med 1994; 179: 609–18.
Klemke C-D, Brade J, Weckesser S, et al. The diagnosis of Sézary syndrome on peripheral blood by flow cytometry requires the use of multiple markers. Br J Dermatol 2008; 159: 871–80.
Morice WG, Kimlinger T, Katzmann JA, et al. Flow cytometric assessment of TCR-V b expression in the evaluation of peripheral blood involvement by T-cell lymphoproliferative disorders: a comparison with conventional T-cell immunophenotyping and molecular genetic techniques. Am J Clin Pathol 2004; 121: 373–83.
Schwab C, Willers J, Niederer E, et al. The use of anti-T-cell receptor-Vbeta antibodies for the estimation of treatment success and phenotypic characterization of clonal T-cell populations in cutaneous T-cell lymphomas. Br J Haematol 2002; 118: 1019–26.
Clark RA, Shackelton JB, Watanabe R, et al. High-scatter T cells: a reliable biomarker for malignant T cells in cutaneous T-cell lymphoma. Blood 2011; 117: 1966–76.
Kirsch IR, Watanabe R, O’Malley JT, et al. TCR sequencing facilitates diagnosis and identifies mature T cells as the cell of origin in CTCL. Sci Transl Med 2015; 7: 308ra158.
Gaide O, Emerson RO, Jiang X, et al. Common clonal origin of central and resident memory T cells following skin immunization. Nat Med 2015; 21: 647–53.
Robins HS, Campregher PV, Srivastava SK, et al. Comprehensive assessment of T-cell receptor-chain diversity in T cells. Blood 2009; 114: 4099–107.
Wu D, Sherwood A, Fromm JR, et al. High-throughput sequencing detects minimal residual disease in acute T lymphoblastic leukemia. Sci Transl Med 2012; 4: 134ra63.
Weng W-K, Armstrong R, Arai S, Desmarais C, Hoppe R, Kim YH. Minimal residual disease monitoring with high-throughput sequencing of T cell receptors in cutaneous T cell lymphoma. Sci Transl Med 2013; 5: 214ra171.
Rook AH, Gelfand JM, Wysocka M, et al. Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma. Blood 2015; 126: 1452–61.
Ponti R, Fierro MT, Quaglino P, et al. TCR γ-chain gene rearrangement by PCR-based genescan: diagnostic accuracy improvement and clonal heterogeneity analysis in multiple cutaneous T-cell lymphoma samples. J Invest Dermatol 2008; 128: 1030–8.
Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105: 3768–85.
Michel L, Jean-Louis F, Begue E, Bensussan A, Bagot M. Use of PLS3, Twist, CD158k/KIR3DL2, and NKp46 gene expression combination for reliable Sézary syndrome diagnosis. Blood 2013; 121: 1477–8.
Nebozhyn M, Loboda A, Kari L, et al. Quantitative PCR on 5 genes reliably identifies CTCL patients with 5% to 99% circulating tumor cells with 90% accuracy. Blood 2006; 107: 3189–96.
Litvinov IV, Jones DA, Sasseville D, Kupper TS. Transcriptional profiles predict disease outcome in patients with cutaneous T-cell lymphoma. Clin Cancer Res 2010; 16: 2106–14.
Litvinov IV, Netchiporouk E, Cordeiro B, et al. The use of transcriptional profiling to improve personalized diagnosis and management of cutaneous T-cell lymphoma (CTCL). Clin Cancer Res 2015; 21: 2820–9.
Shin J, Monti S, Aires DJ, et al. Lesional gene expression profiling in cutaneous T-cell lymphoma reveals natural clusters associated with disease outcome. Blood 2007; 110: 3015–27.
Koboldt DC, Steinberg KM, Larson DE, Wilson RK, Mardis ER. The next-generation sequencing revolution and its impact on genomics. Cell 2013; 155: 27–38.
Behjati S, Tarpey PS. What is next generation sequencing? Arch Dis Child Educ Pract Ed 2013; 98: 236–8.
Bastidas Torres AN, Najidh S, Tensen CP, Vermeer MH. Molecular advances in cutaneous T-cell lymphoma. Semin Cutan Med Surg 2018; 37: 81–6.
Cahill DP, Kinzler KW, Vogelstein B, Lengauer C. Genetic instability and Darwinian selection in tumours. Trends Cell Biol 1999; 9: M57–60.
Dulmage BO, Geskin LJ. Lessons learned from gene expression profiling of cutaneous T-cell lymphoma. Br J Dermatol 2013; 169: 1188–97.
van Doorn R, van Kester MS, Dijkman R, et al. Oncogenomic analysis of mycosis fungoides reveals major differences with Sezary syndrome. Blood 2009; 113: 127–36.
Marquard L, Gjerdrum LM, Christensen IJ, Jensen PB, Sehested M, Ralfkiaer E. Prognostic significance of the therapeutic targets histone deacetylase 1, 2, 6 and acetylated histone H4 in cutaneous T-cell lymphoma. Histopathology 2008; 53: 267–77.
Kiel MJ, Sahasrabuddhe AA, Rolland DCM, et al. Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sézary syndrome. Nat Commun 2015; 6: 8470.
Choi J, Goh G, Walradt T, et al. Genomic landscape of cutaneous T cell lymphoma. Nat Genet 2015; 47: 1011–9.
van Doorn R, Slieker RC, Boonk SE, et al. Epigenomic analysis of Sézary syndrome defines patterns of aberrant DNA methylation and identifies diagnostic markers. J Invest Dermatol 2016; 136: 1876–84.
da Silva Almeida AC, Abate F, Khiabanian H, et al. The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome. Nat Genet 2015; 47: 1465–70.
Kanno Y, Vahedi G, Hirahara K, Singleton K, O’Shea JJ. Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity. Annu Rev Immunol 2012; 30: 707–31.
Ichiyama K, Chen T, Wang X, et al. The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells. Immunity 2015; 42: 613–26.
Qiu L, Liu F, Yi S, et al. Loss of 5-hydroxymethylcytosine is an epigenetic biomarker in cutaneous T-cell lymphoma. J Invest Dermatol 2018; 138: 2388–97.
Serrano M. The tumor suppressor protein p16(INK4a). Exp Cell Res 1997; 237: 7–13.
Navas IC, Algara P, Mateo M, et al. p16(INK4a) is selectively silenced in the tumoral progression of mycosis fungoides. Lab Invest 2002; 82: 123–32.
Patil VS, Zhou R, Rana TM. Gene regulation by non-coding RNAs. Crit Rev Biochem Mol Biol 2014; 49: 16–32.
Collins LJ, Schönfeld B, Chen XS. The epigenetics of non-coding RNA. Handb Epigenetics 2011: 49–61.
Croce CM, Calin GA. miRNAs, cancer, and stem cell division. Cell 2005; 122: 6–7.
Williams M, Cheng YY, Blenkiron C, Reid G. Exploring mechanisms of microRNA downregulation in cancer. MicroRNA 2017; 6: 2–16.
Zimmerman AL, Wu S. MicroRNAs, cancer and cancer stem cells. Cancer Lett 2011; 300: 10–9.
van der Fits L, van Kester MS, Qin Y, et al. MicroRNA-21 expression in CD4+ T cells is regulated by STAT3 and is pathologically involved in Sézary syndrome. J Invest Dermatol 2011; 131: 762–8.
Li C, Song L, Zhang Z, Bai X-X, Cui M-F, Ma L-J. MicroRNA-21 promotes TGF-β1-induced epithelial-mesenchymal transition in gastric cancer through up-regulating PTEN expression. Oncotarget 2016; 7: 66989–7003.
Kopp K, Ralfkiaer U, Mette Gjerdrum L, et al. STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma. Cell Cycle 2013; 12: 1939–47.
Qin Y, Buermans HPJ, van Kester MS, et al. Deep-sequencing analysis reveals that the miR-199a2/214 cluster within DNM3os represents the vast majority of aberrantly expressed microRNAs in Sézary syndrome. J Invest Dermatol 2012; 132: 1520–2.
Wang F, Liu M, Li X, Tang H. MiR-214 reduces cell survival and enhances cisplatin-induced cytotoxicity via down-regulation of Bcl2l2 in cervical cancer cells. FEBS Lett 2013; 587: 488–95.
Wang Y-S, Wang Y-H, Xia H-P, Zhou S-W, Schmid-Bindert G, Zhou C-C. MicroRNA-214 regulates the acquired resistance to gefitinib via the PTEN/AKT pathway in EGFR-mutant cell lines. Asian Pac J Cancer Prev 2012; 13: 255–60.
Kohnken R, McNeil B, Wen J, et al. Preclinical targeting of microRNA-214 in cutaneous T-cell lymphoma (CTCL). J Invest Dermatol 2019; 139: 1966–74.e3.
Kohnken R, Wen J, Mundy-Bosse B, et al. Diminished microRNA-29b level is associated with BRD4-mediated activation of oncogenes in cutaneous T-cell lymphoma. Blood 2018; 131: 771–81.
Amodio N, Stamato MA, Gullà AM, et al. Therapeutic targeting of miR-29b/HDAC4 epigenetic loop in multiple myeloma. Mol Cancer Ther 2016; 15: 1364–75.
Amodio N, Leotta M, Bellizzi D, et al. DNA-demethylating and anti-tumor activity of synthetic miR-29b mimics in multiple myeloma. Oncotarget 2012; 3: 1246–58.
Donati B, Lorenzini E, Ciarrocchi A. BRD4 and cancer: going beyond transcriptional regulation. Mol Cancer 2018; 17: 164.
Zhao X, Tao J. BRD4: epigenetic origin and target of CTCL. Blood 2018; 131: 712–3.
Andrieu G, Belkina AC, Denis GV. Clinical trials for BET inhibitors run ahead of the science. Drug Discov Today Technol 2016; 19: 45–50.
Manso R, Martínez-Magunacelaya N, Eraña-Tomás I, et al. Mycosis fungoides progression could be regulated by microRNAs. PLoS One 2018; 13: e0198477.
Dusílková N, Bašová P, Polívka J, et al. Plasma miR-155, miR-203, and miR-205 are biomarkers for monitoring of primary cutaneous T-cell lymphomas. Int J Mol Sci 2017; 18: 18.
Saraki K, Papadaki M, Piperi C, et al. Importance of circulating miRNAs in CTCL diagnosis. Eur J Cancer 2019; 119: S12.
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70.
Contassot E, French LE. Targeting apoptosis defects in cutaneous T-cell lymphoma. J Invest Dermatol 2009; 129: 1059–61.
Stutz N, Johnson RD, Wood GS, The GS. Fas apoptotic pathway in cutaneous T-cell lymphomas: frequent expression of phenotypes associated with resistance to apoptosis. J Am Acad Dermatol 2012; 67: 1327.e1–10.
Ungewickell A, Bhaduri A, Rios E, et al. Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2. Nat Genet 2015; 47: 1056–60.
Bonizzi G, Karin M. The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 2004; 25: 280–8.
Chang T-P, Poltoratsky V, Vancurova I. Bortezomib inhibits expression of TGF-β1, IL-10, and CXCR4, resulting in decreased survival and migration of cutaneous T cell lymphoma cells. J Immunol 2015; 194: 2942–53.
Kießling MK, Oberholzer PA, Mondal C, et al. High-throughput mutation profiling of CTCL samples reveals KRAS and NRAS mutations sensitizing tumors toward inhibition of the RAS/RAF/MEK signaling cascade. Blood 2011; 117: 2433–40.
Chakraborty A, Robey R, Gillet J-P, et al. Abstract B9: Activated MAPK pathway mediates resistance to romidepsin via Bim degradation in romidepsin-selected HuT 78 Cells. Clin Cancer Res 2012; 18: B9.
Kremer M, Sliva K, Klemke C-D, Schnierle BS. Cutaneous T-cell lymphoma cells are sensitive to rapamycin. Exp Dermatol 2010; 19: 800–5.
Chang L-W, Patrone CC, Yang W, et al. An integrated data resource for genomic analysis of cutaneous T-cell lymphoma. J Invest Dermatol 2018; 138: 2681–3.
Wang L, Ni X, Covington KR, et al. Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes. Nat Genet 2015; 47: 1426–34.
Cairns P, Polascik TJ, Eby Y, et al. Frequency of homozygous deletion at p16/CDKN2 in primary human tumours. Nat Genet 1995; 11: 210–2.
Woollard WJ, Pullabhatla V, Lorenc A, et al. Candidate driver genes involved in genome maintenance and DNA repair in Sézary syndrome. Blood 2016; 127: 3387–97.
Goldsby RA, Kindt TJ, Osborne BA, Kuby J. Immunology. New York: Freeman WH, 2000.
Courtney AH, Lo W-L, Weiss A. TCR signaling: mechanisms of initiation and propagation. Trends Biochem Sci 2018; 43: 108–23.
Yoo HY, Kim P, Kim WS, et al. Frequent CTLA4-CD28 gene fusion in diverse types of T-cell lymphoma. Haematologica 2016; 101: 757–63.
Ostrand-Rosenberg S, Horn LA, Haile ST. The programmed death-1 immune-suppressive pathway: barrier to antitumor immunity. J Immunol 2014; 193: 3835–41.
Samimi S, Benoit B, Evans K, et al. Increased programmed death-1 expression on CD4+ T cells in cutaneous T-cell lymphoma: implications for immune suppression. Arch Dermatol 2010; 146: 1382–8.
Kantekure K, Yang Y, Raghunath P, et al. Expression patterns of the immunosuppressive proteins PD-1/CD279 and PD-L1/CD274 at different stages of cutaneous T-cell lymphoma/mycosis fungoides. Am J Dermatopathol 2012; 34: 126–8.
Vaqué JP, Gómez-López G, Monsálvez VV, et al. PLCG1 mutations in cutaneous T-cell lymphomas. Blood 2014; 123: 2034–43.
Dai J, Almazan T, Kim Y, Khodadoust M. Pembrolizumab in systemic and cutaneous T-cell lymphoma. Ann Lymphoma 2018: 2.
Hart M, Walch-Rückheim B, Friedmann KS, et al. miR-34a: a new player in the regulation of T cell function by modulation of NF-κB signaling. Cell Death Dis 2019; 10.
Williams TM, Moolten D, Burlein J, et al. Identification of a zinc finger protein that inhibits IL-2 gene expression. Science 1991; 254: 1791–4.
Mishra A, Kwiatkowski S, Sullivan L, et al. Epigenetic disruption of ZEB1 binding causes constitutive activation of IL-15 in cutaneous T-cell lymphoma. Blood 2015; 126.
Caprini E, Bresin A, Cristofoletti C, et al. Loss of the candidate tumor suppressor ZEB1 (TCF8, ZFHX1A) in Sézary syndrome. Cell Death Dis 2018; 9: 1178.
Park J, Yang J, Wenzel AT, et al. Genomic analysis of 220 CTCLs identifies a novel recurrent gain-of-function alteration in RLTPR (p.Q575E). Blood 2017; 130: 1430–40.
Liao W, Schones DE, Oh J, et al. Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor α-chain expression. Nat Immunol 2008; 9: 1288–96.
O’Shea JJ, Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 2012; 36: 542–50.
Stritesky GL, Muthukrishnan R, Sehra S, et al. The transcription factor STAT3 is required for T helper 2 cell development. Immunity 2011; 34: 39–49.
Döbbeling U. Transcription factor profiling shows new ways towards new treatment options of cutaneous T cell lymphomas. Curr Drug Discov Technol 2007; 4: 24–30.
Nielsen M, Kaestel CG, Eriksen KW, et al. Inhibition of constitutively activated Stat3 correlates with altered Bcl-2/Bax expression and induction of apoptosis in mycosis fungoides tumor cells. Leukemia 1999; 13: 735–8.
Qin J-Z, Kamarashev J, Zhang C-L, Dummer R, Burg G, Döbbeling U. Constitutive and interleukin-7- and interleukin-15-stimulated DNA binding of STAT and novel factors in cutaneous T cell lymphoma cells. J Invest Dermatol 2001; 117: 583–9.
Netchiporouk E, Litvinov IV, Moreau L, Gilbert M, Sasseville D, Duvic M. Deregulation in STAT signaling is important for cutaneous T-cell lymphoma (CTCL) pathogenesis and cancer progression. Cell Cycle 2014; 13: 3331–5.
van der Fits L, Out-Luiting JJ, van Leeuwen MA, et al. Autocrine IL-21 stimulation is involved in the maintenance of constitutive STAT3 activation in Sézary syndrome. J Invest Dermatol 2012; 132: 440–7.
Zhang Q, Wang HY, Marzec M, Raghunath PN, Nagasawa T, Wasik MA. STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. Proc Natl Acad Sci USA 2005; 102: 6948–53.
Lorenz U. SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels. Immunol Rev 2009; 228: 342–59.
Witkiewicz A, Raghunath P, Wasik A, et al. Loss of SHP-1 tyrosine phosphatase expression correlates with the advanced stages of cutaneous T-cell lymphoma. Hum Pathol 2007; 38: 462–7.
Lauenborg B, Christensen L, Ralfkiaer U, et al. Malignant T cells express lymphotoxin α and drive endothelial activation in cutaneous T cell lymphoma. Oncotarget 2015; 6: 15235–49.
Krejsgaard T, Vetter-Kauczok CS, Woetmann A, et al. Jak3- and JNK-dependent vascular endothelial growth factor expression in cutaneous T-cell lymphoma. Leukemia 2006; 20: 1759–66.
Gallardo F, Sandoval J, Díaz-Lagares A, et al. Notch1 pathway activation results from the epigenetic abrogation of notch-related microRNAs in mycosis fungoides. J Invest Dermatol 2015; 135: 3144–52.
Kamstrup MR, Gjerdrum LMR, Biskup E, et al. Notch1 as a potential therapeutic target in cutaneous T-cell lymphoma. Blood 2010; 116: 2504–12.
Shalabi D, Bistline A, Alpdogan O, et al. Immune evasion and current immunotherapy strategies in mycosis fungoides (MF) and Sézary syndrome (SS). Chinese Clin Oncol 2019; 8: 11–111.
Fujii K. New therapies and immunological findings in cutaneous T-cell lymphoma. Front Oncol 2018; 8: 198.
Wong HK. Immunopathogenesis of mycosis fungoides/Sézary syndrome (cutaneous T-cell lymphoma). G Ital Dermatol Venereol 2008; 143: 375–83.
Dan N, Setua S, Kashyap VK, et al. Antibody-drug conjugates for cancer therapy: chemistry to clinical implications. Pharmaceuticals 2018; 11: 32.
Bagot M. New targeted treatments for cutaneous T-cell Lymphomas. Indian J Dermatol 2017; 62: 142.
Tsuchikama K, An Z. Antibody-drug conjugates: recent advances in conjugation and linker chemistries. Protein Cell 2018; 9: 33–46.
Ollila TA, Sahin I, Olszewski AJ. Mogamulizumab: a new tool for management of cutaneous T-cell lymphoma. Onco Targets Ther 2019; 12: 1085–94.
Beck A, Reichert JM. Marketing approval of mogamulizumab. MAbs 2012; 4: 419–25.
Ni X, Jorgensen JL, Goswami M, et al. Reduction of regulatory T cells by mogamulizumab, a defucosylated anti-CC chemokine receptor 4 antibody, in patients with aggressive/refractory mycosis fungoides and Sezary syndrome. Clin Cancer Res 2015; 21: 274–85.
Kim YH, Bagot M, Pinter-Brown L, et al. Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. Lancet Oncol 2018; 19: 1192–204.
Scarisbrick J, Geskin LJ, Bagot M, et al. Efficacy of mogamulizumab in previously treated patients with less advanced mycosis fungoides (MF): results from the MAVORIC study. Eur J Cancer 2019; 119: S31–2.
Clark RA, Watanabe R, Teague JE, et al. Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumabtreated CTCL patients. Sci Transl Med 2012; 4: 117ra7.
Jiang L, Yuan CM, Hubacheck J, et al. Variable CD52 expression in mature T cell and NK cell malignancies: implications for alemtuzumab therapy. Br J Haematol 2009; 145: 173–9.
de Masson A, Guitera P, Brice P, et al. Long-term efficacy and safety of alemtuzumab in advanced primary cutaneous T-cell lymphomas. Br J Dermatol 2014; 170: 7204.
Thonnart N, Caudron A, Legaz I, Bagot M, Bensussan A, Marie-Cardine A. KIR3DL2 is a coinhibitory receptor on Sezary syndrome malignant T cells that promotes resistance to activation-induced cell death. Blood 2014; 124: 3330–2.
Carter JB, Goyal A, McDivitt Duncan L. Atlas of Cutaneous Lymphomas. Cham: Springer International Publishing, 2015.
Poszepczynska-Guigné E, Schiavon V, D’Incan M, et al. CD158k/KIR3DL2 is a new phenotypic marker of Sezary cells: relevance for the diagnosis and follow-up of Sezary syndrome. J Invest Dermatol 2004; 122: 820–3.
Wechsler J, Bagot M, Nikolova M, et al. Killer cell immunoglobulin-like receptor expression delineates in situ Sézary syndrome lymphocytes. J Pathol 2003; 199: 77–83.
Bagot M, Porcu P, Marie-Cardine A, et al. IPH4102, a first-in-class anti-KIR3DL2 monoclonal antibody, in patients with relapsed or refractory cutaneous T-cell lymphoma: an international, first-in-human, open-label, phase 1 trial. Lancet Oncol 2019; 20: 1160–70.
van der Weyden CA, Pileri SA, Feldman AL, Whisstock J, Prince HM. Understanding CD30 biology and therapeutic targeting: a historical perspective providing insight into future directions. Blood Cancer J 2017; 7: e603.
Yi JH, Kim SJ, Kim WS. Brentuximab vedotin: clinical updates and practical guidance. Blood Res 2017; 52: 243.
Mehra T, Ikenberg K, Moos RM, et al. Brentuximab as a treatment for CD30+ mycosis fungoides and Sézary syndrome. JAMA Dermatol 2015; 151: 73.
Scarisbrick J, Horwitz SM, Prince HM, et al. Brentuximab vedotin (BV) versus physician’s choice (PC) of methotrexate or bexarotene in adult patients with previously treated CD30-positive cutaneous T-cell lymphoma (CTCL; mycosis fungoides MF] or primary cutaneous anaplastic large cell lymphoma cALCL]): final time to next therapy (TTNT) results from the phase 3 ALCANZA study. Eur J Cancer 2019; 119: S31.
Stranzenbach R, Stadler R. The combination of brentuximab vedotin with skin-directed therapies in response to PD extend the time to the next therapeutic line. Eur J Cancer 2019; 119: S33.
Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis 2010; 31: 27–36.
Fardi M, Solali S, Farshdousti Hagh M. Epigenetic mechanisms as a new approach in cancer treatment: an updated review. Genes Dis 2018; 5: 304–11.
Kohnken R, Mishra A. MicroRNAs in cutaneous T-cell lymphoma: the future of therapy. J Invest Dermatol 2019; 139: 528–34.
Alabdulaali MK. The role of JAK2 abnormalities in hematologic neoplasms. Hematol Rep 2009; 1: 10.
Querfeld C, Foss FM, Pinter-Brown LC, et al. Phase 1 study of the safety and efficacy of MRG-106, a synthetic inhibitor of microRNA-155, in CTCL patients. Blood 2017; 130.
Scarisbrick J, Querfeld C, James A, et al. SOLAR: a phase 2, global, randomized, active comparator study to investigate the efficacy and safety of cobomarsen in subjects with mycosis fungoides (MF). Eur J Cancer 2019; 119: S32.
Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res 2011; 21: 381–95.
Lopez AT, Bates S, Geskin L. Current status of HDAC inhibitors in cutaneous T-cell lymphoma. Am J Clin Dermatol 2018; 19: 805–19.
Rangwala S, Zhang C, Duvic M. HDAC inhibitors for the treatment of cutaneous T-cell lymphomas. Future Med Chem 2012; 4: 471–86.
Pralatrexate + romidepsin in relapsed/refractory lymphoid malignancies. ClinicalTrials.gov.
Romidepsin plus oral 5-azacitidine in relapsed/refractory lymphoid malignancies. ClinicalTrials.gov.
Stadler R, Scarisbrick J, Knobler R, et al. A multicenter, double blind, randomized, placebo-controlled, phase II trial to evaluate resminostat for maintenance treatment of patients with advanced stage (stage IIB-IVB) mycosis fungoides (MF) or Sézary syndrome (SS) that have achieved disease control with systemic therapy: the RESMAIN study. Eur J Cancer 2019; 119: S32.
Kantekure K, Yang Y, Raghunath P, et al. Expression patterns of the immunosuppressive proteins PD-1/CD279 and PD-L1/CD274 at different stages of cutaneous T-cell lymphoma/mycosis fungoides. Am J Dermatopathol 2012; 34: 126–8.
Ilcus C, Bagacean C, Tempescul A, et al. Immune checkpoint blockade: the role of PD-1-PD-L axis in lymphoid malignancies. Onco Targets Ther 2017; 10: 2349–63.
Dai J, Almazan T, Kim Y, Khodadoust M. Pembrolizumab in systemic and cutaneous T-cell lymphoma. Ann Lymphoma 2018; 1: 1–11.
Suraweera A, O’Byrne KJ, Richard DJ. Combination therapy with histone deacetylase inhibitors (HDACi) for the treatment of cancer: achieving the full therapeutic potential of HDACi. Front Oncol 2018; 8: 92.
PARCT: Trial of atezolizumab in relapsed/refractory cutaneous t cell lymphoma (CTCL). ClinicalTrials.gov.
Yamamoto N, Muro K, Ishii H, et al. LBA 17 Anti-CC-chemokine receptor 4 (CCR4) antibody mogamulizumab (Moga) and nivolumab (Nivo) combination phase I study in patients with advanced or metastatic solid tumors. Ann Oncol 2017; 28.
Liao J, Lin J, Lin D, et al. Down-regulation of miR-214 reverses erlotinib resistance in non-small-cell lung cancer through up-regulating LHX6 expression. Sci Rep 2017; 7: 781.
Mishra A, La Perle K, Kwiatkowski S, et al. Mechanism, consequences, and therapeutic targeting of abnormal IL15 signaling in cutaneous T-cell lymphoma. Cancer Discov 2016; 6: 986–1005.
van Kester MS, Borg MK, Zoutman WH, et al. A meta-analysis of gene expression data identifies a molecular signature characteristic for tumor-stage mycosis fungoides. J Invest Dermatol 2012; 132: 2050–9.
Karatzas E, Kolios G, Spyrou GM. An Application of Computational Drug Repurposing Based on Transcriptomic Signatures. New York: Humana Press, 2019, 149–77.
McGirt LY, Jia P, Baerenwald DA, et al. Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides. Blood 2015; 126: 508–19.
Prasad A, Rabionet R, Espinet B, et al. Identification of gene mutations and fusion genes in patients with Sézary syndrome. J Invest Dermatol 2016; 136: 1490–9.
Iżykowska K, Przybylski GK, Gand C, et al. Genetic rearrangements result in altered gene expression and novel fusion transcripts in Sézary syndrome. Oncotarget 2017; 8: 39627–39.
Ballabio E, Mitchell T, van Kester MS, et al. MicroRNA expression in Sezary syndrome: identification, function, and diagnostic potential. Blood 2010; 116: 1105–13.
Narducci MG, Arcelli D, Picchio MC, et al. MicroRNA profiling reveals that miR-21, miR486 and miR-214 are upregulated and involved in cell survival in Sézary syndrome. Cell Death Dis 2011; 2: e151.
Ralfkiaer U, Hagedorn PH, Bangsgaard N, et al. Diagnostic microRNA profiling in cutaneous T-cell lymphoma (CTCL). Blood 2011; 118: 5891–900.
van Kester MS, Ballabio E, Benner MF, et al. miRNA expression profiling of mycosis fungoides. Mol Oncol 2011; 5: 273–80.
Benner MF, Ballabio E, Kester MS, et al. Primary cutaneous anaplastic large cell lymphoma shows a distinct miRNA expression profile and reveals differences from tumor-stage mycosis fungoides. Exp Dermatol 2012; 21: 632–4.
Lee CS, Ungewickell A, Bhaduri A, et al. Transcriptome sequencing in Sezary syndrome identifies Sezary cell and mycosis fungoides-associated lncRNAs and novel transcripts. Blood 2012; 120: 3288–97.
Manfè V, Biskup E, Rosbjerg A, et al. miR-122 regulates p53/Akt signalling and the chemotherapy-induced apoptosis in cutaneous T-cell lymphoma. PLoS One 2012; 7: e29541.
Marosvári D, Téglási V, Csala I, et al. Altered microRNA expression in folliculotropic and transformed mycosis fungoides. Pathol Oncol Res 2015; 21: 821–5.
Sandoval J, Díaz-Lagares A, Salgado R, et al. MicroRNA expression profiling and DNA methylation signature for deregulated microRNA in cutaneous T-cell lymphoma. J Invest Dermatol 2015; 135: 1128–37.
Papadavid E, Braoudaki M, Bourdakou M, et al. Aberrant microRNA expression in tumor mycosis fungoides. Tumor Biol 2016; 37: 14667–75.
Lindahl LM, Besenbacher S, Rittig AH, et al. Prognostic miRNA classifier in early-stage mycosis fungoides: development and validation in a Danish nationwide study. Blood 2018; 131: 759–70.
Queen D, Lopez A, Geskin LJ. Merging therapies for cutaneous T-cell lymphoma. Medicine Matters 2019.
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Papadaki, M., Saraki, K., Karagianni, F. et al. Cutaneous T-cell lymphoma: aetiopathogenesis and current diagnostic and therapeutic developments. Eur J Dermatol 30, 85–102 (2020). https://doi.org/10.1684/ejd.2020.3712
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DOI: https://doi.org/10.1684/ejd.2020.3712