Abstract
Sézary syndrome (SS) is an aggressive cutaneous T cell lymphoma with pruritic skin inflammation and immune dysfunction, driven by neoplastic, clonal memory T cells in both peripheral blood and skin. To gain insight into abnormal gene expression promoting T cell dysfunction, lymphoproliferation and transformation in SS, we first compared functional transcriptomic profiles of both resting and activated CD4+CD45RO+ T cells from SS patients and normal donors to identified differential expressed genes. Next, a meta-analysis was performed to compare our SS data to public microarray data from a novel benign disease control, lymphocytic-variant hypereosinophilic syndrome (L-HES). L-HES is a rare, clonal lymphoproliferation of abnormal memory T cells that produces similar clinical symptoms as SS, including severe pruritus and eosinophilia. Comparison revealed gene sets specific for either SS (370 genes) or L-HES (519 genes), and a subset of 163 genes that were dysregulated in both SS and L-HES T cells compared to normal donor T cells. Genes confirmed by RT-qPCR included elevated expression of PLS3, TWIST1 and TOX only in SS, while IL17RB mRNA was increased only in L-HES. CDCA7 was increased in both diseases. In an L-HES patient who progressed to peripheral T cell lymphoma, the malignant transformation identified increases in the expression of CDCA7, TIGIT, and TOX, which are highly expressed in SS, suggesting that these genes contribute to neoplastic transformation. In summary, we have identified gene expression biomarkers that implicate a common transformative mechanism and others that are unique to differentiate SS from L-HES.
Highlights
Sézary Syndrome (SS) is a rare and aggressive leukemic form of cutaneous T cell lymphoma (CTCL), characterized by pruritic erythroderma, lymphadenopathy, and leukemic T cells in the peripheral blood
Sézary syndrome (SS) arises from the malignant transformation of skin homing memory T cells with Th2 bias, while lymphocytic-variant hypereosinophilic syndrome (L-HES) is a benign lymphoproliferation of phenotypically similar T cells
We present the first comparison of differential gene expression in SS and L-HES to gain insight into these two similar diseases arising from memory T cells
Summary
Sézary Syndrome (SS) is a rare and aggressive leukemic form of cutaneous T cell lymphoma (CTCL), characterized by pruritic erythroderma, lymphadenopathy, and leukemic T cells in the peripheral blood. The etiology of SS is unclear, but it is thought to develop from neoplastic transformation of mature CD4 T cells with Th2 bias and skin homing properties. SS can arise spontaneously, or develop in patients with a prior diagnosis of mycosis fungoides, a more skin-tropic and indolent form of CTCL. Lymphocytic-variant hypereosinophilic syndrome (L-HES) has clinical findings very similar to SS, and is derived from a benign lymphoproliferation of clonal T cells with skin and blood tropism. Common dermatological manifestations of L-HES include pruritus, erythroderma, eczema, urticaria and angioderma [8,9,10]. These features make L-HES a valuable disease control for molecular studies of SS pathogenesis
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