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Sézary Syndrome Is a Unique Cutaneous T-Cell Lymphoma As Leukemia (2008) 22, 393–399 & 2008 Nature Publishing Group All rights reserved 0887-6924/08 $30.00 www.nature.com/leu ORIGINAL ARTICLE Se´zary syndrome is a unique cutaneous T-cell lymphoma as identified by an expanded gene signature including diagnostic marker molecules CDO1 and DNM3 N Booken1,11, A Gratchev1,11, J Utikal1, C Wei2,XYu3, M Qadoumi1, M Schmuth4, N Sepp4, D Nashan5, K Rass6,TTu¨ting7, C Assaf8, E Dippel1,9, R Stadler10, C-D Klemke1 and S Goerdt1 1Department of Dermatology, Venereology and Allergology, University Medical Centre Mannheim, Ruprecht Karl University of Heidelberg, Mannheim, Germany; 2Institute of Medical Statistics, University Medical Centre Mannheim, Ruprecht Karl University of Heidelberg, Mannheim, Germany; 3Medical Research Center (ZMF), University Medical Centre Mannheim, Ruprecht Karl University of Heidelberg, Mannheim, Germany; 4Department of Dermatology, Innsbruck Medical University, Innsbruck, Austria; 5Department of Dermatology, University of Freiburg, Freiburg, Germany; 6Department of Dermatology, The Saarland University Hospital, Homburg/Saar, Germany; 7Department of Dermatology, University of Bonn, Bonn, Germany; 8Department of Dermatology, Charite-University Medicine Berlin, Berlin, Germany; 9Department of Dermatology, Academic Medical Centre, Lemgo, Germany and 10Department of Dermatology, Academic Medical Centre, Minden, Germany Sezary syndrome (SS) is a rare, aggressive CD4 þ cutaneous While MF usually is a slowly progressive disease, SS runs a more T-cell lymphoma (CTCL); molecular traits differentiating SS aggressive course with a high mortality rate and a median survival from nonleukemic mycosis fungoides (MF) and from inflamma- time of 2–4 years. The probability of survival in CTCL can be tory skin diseases (ID) are not sufficiently characterized. accurately predicted by a formula based on the clinical CTCL- Peripheral blood mononuclear cells (PBMC) of 10 SS patients 1 and 10 healthy donors (HD) were screened by Affymetrix severity index (CTCL-SI) that evaluates the involvement of the skin, 2 U133Plus2.0 chips for differential gene expression. Ten candi- lymph nodes, blood and visceral organs. date genes were confirmed by qRT-PCR to be significantly Sezary cells are malignant circulating CD4 þ T cells that þ overexpressed in CD4 T cells of SS versus HD/ID. For easier derive from the same T-cell clone as the malignant T cells in skin clinical use, these genes were re-analyzed in PBMC; qRT-PCR and other organs as demonstrated by T-cell receptor (TCR) gene confirmed five novel (DNM3, IGFL2, CDO1, NEDD4L, KLHDC5) 3,4 and two known genes (PLS3, TNFSF11) to be significantly rearrangement analysis studies. The detection of Sezary cells overexpressed in SS. Multiple logistic regression analysis in the peripheral blood is primarily based on morphological revealed that CDO1 and DNM3 had the highest discriminative features such as cerebriform nuclei; therefore, ‘Sezary cells’ may power in combination. Upon comparison of PBMC and skin be detected in healthy individuals as well as in inflammatory samples of SS versus MF, CDO1 and DNM3 were found dermatoses. As a consequence, an arbitrary threshold has been upregulated only in SS. Using anti-CDO1 antisera, differential set at 5% (20%) Sezary cells among peripheral blood mono- expression of CDO1 protein was confirmed in SS CD4 þ T cells. Interestingly, DNM3 and CDO1 are known to be regulated by nuclear cells (peripheral blood lymphocytes) for the diagnosis of SS-associated transcription factors TWIST1 and c-myb, respec- SS in the blood. Loss of CD26 or CD7, expression of CD158k/ tively. Furthermore, CDO1 catalyzes taurine synthesis and KIR3DL2, analysis of Her2 neu gene copy number, and lack of taurine inhibits apoptosis and promotes chemoprotection. In T regulatory cells may be informative,5,6 but only apply to a summary, CDO1 and DNM3 may improve the diagnosis of SS subpopulation of SS patients. Recently, multi-gene qRT-PCR was and open novel clues to its pathogenesis. proposed to improve the molecular diagnosis of SS cells in the Leukemia (2008) 22, 393–399; doi:10.1038/sj.leu.2405044; peripheral blood, but the method still awaits confirmation by published online 22 November 2007 7 Keywords: Se´zary syndrome; DNA arrays; cysteine dioxygenase; other groups and validation using independent patient samples. dynamin 3; diagnostic markers In SS and MF, chemotherapy does not improve survival, but impairs quality of life; due to frequent recurrences, allogeneic bone marrow transplantation is no successful treatment option either. Stage-adapted therapy as pursued currently by most groups Introduction aims at mitigating the course of the disease, but a potentially curative treatment regimen for SS or MF does not exist, indicating the urgent necessity to identify novel therapeutic targets. Cutaneous T-cell lymphomas (CTCL) are a group of lymphoproli- We here performed Affymetrix microarray-based gene ex- ferative disorders that are characterized by localization of malignant pression profiling of SS peripheral blood mononuclear cells T lymphocytes in the skin, mainly in the epidermis. The classical (PBMC) versus healthy controls followed by qRT-PCR and forms of CTCL are plaque-type mycosis fungoides (MF) and Sezary statistical analysis to identify and validate candidate genes as syndrome (SS). SS is a rare, leukemic variant of CTCL that typically novel diagnostic markers and putative therapeutic targets for the presents with erythroderma, peripheral lymphadenopathy, severe disease. We also assessed the predictive capacity of SS- pruritus and malignant, circulating T lymphocytes, the Sezary cells. associated genes identified by others. Correspondence: Dr N Booken, Department of Dermatology, Venerolo gy and Allergology, University Medical Center Mannheim, Ruprecht-Karl University Heidelberg, Theodor-Kutzer-Ufer 1-3, Patients, materials and methods D-68167 Mannheim, Germany. E-mail: [email protected] 11These authors contributed equally to this work. Patients Received 18 April 2007; revised 13 October 2007; accepted 24 A total of 41 CTCL patients were included in the study, 27 October 2007; published online 22 November 2007 patients with SS (14 male and 13 female), median age 68 years, Se´zary syndrome gene expression N Booken et al 394 ranging from 48 to 83 years, stage III/IVA and 14 patients with U133 Plus 2.0 Arrays from Affymetrix (ten control samples and MF (10 male and 4 female), median age 59 years, ranging from ten samples from SS patients) were utilized. Raw data from 16 to 95 years, stage IB-IVA. The patients were diagnosed Affymetrix CEL files were analyzed using SAS software package according to the WHO-EORTC classification of cutaneous Microarray Solution version 1.3 (SAS Institute, Cary NC). Gene lymphomas and the criteria of the International Society of annotation was obtained through the Affymetrix NetAffx website Cutaneous Lymphomas. The extent of CTCL involvement was (http://www.affymetrix.com/analysis/index.affx). The quality quantified by the CTCL-SI.2 Analysis of the TCR g or b chain control, normalisation and statistical modeling were performed genes was performed using the well-established polymerase by array group correlation, mixed model normalisation and chain reaction-based GeneScan technique.3 All patients with SS mixed model analysis, respectively. Analysis of differential gene had erythroderma, peripheral lymphadenopathies, a highly expression was based on a loglinear mixed model of perfect elevated CD4/CD8 ratio and atypical circulating Sezary cells matches,8 where group (SS or control) were considered to be in the blood (Supplementary Table 1). For comparative analysis, with constant effects and the chip ID with random effect. blood samples were obtained from 10 healthy donors (4 males and 6 females, median age 57 years, ranging from 34 to 84 years). In addition for qRT-PCR experiments, peripheral blood Real-time RT–PCR analysis samples and lesional skin biopsy specimens of 24 patients with RT–PCR analysis was used to determine lack of gene expression different inflammatory skin diseases (ID) such as psoriasis (16 of candidate genes in CD4 þ T cells of healthy donors and ID patients, 13 male and 3 female, median age 53 years, ranging versus SS patients. Primers used were from Metabion (Martins- from 28 to 76 years), atopic dermatitis (6 patients, 5 male and 1 ried, Germany); primer sequences and the standard RT–PCR female, median age 46 years, ranging from 24 to 78 years) and procedures applied will be supplied by the authors upon erysipelas (2 patients, 1 male and 1 female of 28 and 78 years of request. Real-time PCR analysis was performed using TaqMan age) were obtained. Furthermore 15 additional samples of PCR master mix (Applied Biosystems, Darmstadt, Germany) healthy donors (5 male and 10 female, median age 48 years, together with TaqMan probes and primers (MWG-Biotech, ranging from 25 to 89 years) and peripheral blood T cells Martinsried, Germany) using standard conditions. Each primer activated for 3 days with phytohemagglutinin were also and probe concentration was optimized before use. The included in the study (Supplementary Text 1). Sezary cell lines sequences and concentrations used for quantification of the (SeAx, HH and Hut 78), MF cell line (Myla), leukemia cell lines selected genes are listed in the Supplementary Table 2. Human (Molt, Peer) were used as a calibrators for real-time RT–PCR GAPD was used as an internal control. The experiments were analysis. The study was approved by the Medical Ethics
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