Aberrant Expression of the Tyrosine Kinase Receptor EphA4 and the Transcription Factor Twist in Sézary Syndrome Identified by Gene Expression Analysis

Abstract

Sézary syndrome (Sz) is a malignancy of CD4؉ memory skin-homing T cells and presents with erythroderma, lymphadenopathy, and peripheral blood involvement. To gain more insight into the molecular features of Sz, oligonucleotide array analysis was performed comparing gene expression patterns of CD4؉ T cells from peripheral blood of patients with Sz with those of patients with erythroderma secondary to dermatitis and healthy controls. Using unsupervised hierarchical clustering gene, expression patterns of T cells from patients with Sz were classified separately from those of benign T cells. One hundred twenty-three genes were identified as significantly differentially expressed and had an average fold change exceeding 2. T cells from patients with Sz demonstrated decreased expression of the following hematopoietic malignancy-linked tumor suppressor genes: TGF-␤ receptor II, Mxi1, Riz1, CREB-binding protein, BCL11a, STAT4, and Forkhead Box O1A. Moreover, the tyrosine kinase receptor EphA4 and the potentially oncogenic transcription factor Twist were highly and selectively expressed in T cells of patients with Sz. High expression of EphA4 and Twist was also observed in lesional skin biopsy specimens of a subset of patients with cutaneous T cell lymphomas related to Sz, whereas their expression was nearly undetectable in benign T cells or in skin lesions of patients with inflammatory dermatoses. Detection of EphA4 and Twist may be used in the molecular diagnosis of Sz and related cutaneous T-cell lymphomas. Furthermore, the membrane-bound EphA4 receptor may serve as a target for directed therapeutic intervention.

Natural killer cell lymphoma shares strikingly similar molecular features with a group of non-hepatosplenic γδ T-cell lymphoma and is highly sensitive to a novel aurora kinase A inhibitor in vitro

“…When gd-PTCL (NHS) subtype was compared with HSTCL, similar differential expression as noted with NKCL was observed aside from the TCR complex-related transcripts. Notably, the CT molecules GNLY (33-fold), GZMB (11-fold), GZMM (4-fold) and transcription factor TWIST1 (19-fold) previously shown to be highly expressed in Sézary syndrome 30 and pan T-cell marker CD7 (8-fold) were significantly up-regulated in gd-PTCL (NHS).…”

Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1

“…53 The Ephrin family of tyrosine kinase receptors have also been shown to activate the JAK-STAT3 pathway. 54 Overexpression of one Ephrin family member, EphA4, has been reported in several human cancers, including SS, 55 and therefore it represents a potential mechanism for aberrant JAK-STAT3 activation.…”

Sézary syndrome is a unique cutaneous T-cell lymphoma as identified by an expanded gene signature including diagnostic marker molecules CDO1 and DNM3

“…While DNM3, IGFL2, CDO1, NEDD4L and KLHDC5 are described to be overexpressed in Sezary cells for the first time in this study, PLS3 and TNFSF11 have previously been noted to be highly expressed in Sezary cells. [11][12][13] While single gene analysis with any of these seven genes may suffice in CD4 þ T-cell samples, high sensitivity and high specificity in PBMC samples is achieved preferentially by combined analysis of mRNA expression levels of CDO1 and DNM3. Analysis of CDO1 and DNM3 in PBMC and skin samples of SS versus MF patients also indicated that these markers identify SS as a molecularly unique CTCL.…”

“…11,13,14 This is probably due to the differences in microarray platforms used by the different groups, 11,13 to strategic differences in identifying common versus differential traits of SS and MF, 11,13,14 and to selection of control populations including Th2 T cells. 13 Despite the differences between previous gene profiling studies in SS, our microarray analysis partially confirmed the results of those two studies comparing SS PBMCs/CD4 þ T cells with normal donors. 13,14 Since the analysis of whole gene expression profiles is an expensive and complicated method, the markers identified by microarray experiments are usually used for the design of real-time PCR-based test systems.…”