Lessons learned from gene expression profiling of cutaneous T-cell lymphoma

Abstract

Gene expression studies of cutaneous T-cell lymphoma (CTCL) span a decade, yet pathogenesis is poorly understood and diagnosis remains a challenge. This review examines the varied approaches to gene expression analysis of CTCL, with emphasis on cell populations, control selection, and expression data collection. Despite discordant results, several dysregulated genes have been identified across multiple studies including PLS3, KIR3DL2, TWIST1, and STAT4. Here, we provide an overview of the most consistently expressed genes across different studies and bring them together through common pathways biologically relevant to CTCL. Four pathways, evasion of activation-induced cell death, T-helper 2 lymphocyte differentiation, TGF-β receptor expression, and TNF receptor ligands, appear to encompass the most frequently affected genes, hypothetically providing insight to the disease pathogenesis.

Ectopic expression of embryonic stem cell and other developmental genes in cutaneous T-cell lymphoma

“…27,28 PLS3 (Plastin 3) is an actin binding protein, which is also normally not expressed in T cells. 6,29 Our RT-PCR analysis confirms that BLK, POU2AF, TOX, EVA1, and PLS3 are expressed in CTCL lesional skin biopsies (Fig. 2).…”

“…27,51 In addition, recent translational experimental work revealed that TOX expression, which is usually silenced in mature T cells, can be used as a robust prognostic and diagnostic marker for MF and SS, 52,53 while PLS3 actin binding protein, which is usually not expressed in T cells is consistently expressed in CTCL. 6,29,54,55 A growing body of literature documents that ectopic expression of these genes in CTCL is not a mere indication of deregulated cellular processes, but an important mechanism of tumorigenesis and cancer progression. Our study confirms that select thymocyte development genes (e.g., EVA1 and TOX), B cell-specific genes (POU2AF and BLK) and PLS3 are expressed in CTCL lesional skin and in patient-derived cell lines.…”

“…[3][4][5][6] In addition, several studies identified recurrent chromosomal aberrations in MF/SS. [7][8][9][10][11][12] While much research is focused on investigation of known oncogenes and tumor suppressor genes in CTCL, 6,[13][14][15] recent reports suggest that it is also important to look for genes that could be erroneously expressed in this cancer. 16 Ectopic expression of oncodevelopmental genes (e.g., a-Fetoprotein, H19 and Sonic Hedgehog signaling genes), ESC genes (e.g., OCT4…”

Interleukin-13 is overexpressed in cutaneous T-cell lymphoma cells and regulates their proliferation

“…Malignant CTCL cells were identified both by CD4 positivity and TOX expression. [49][50][51] Indeed, TOX is only expressed by ;60% of CD4 1 T cells in skin biopsies from patients with confirmed CTCL diagnosis, and it is not expressed by NS or skin from AD ( Figure 1B-C), a benign inflammatory skin condition that presents some clinical and histologic features common to CTCL 50,52 and harbors a large number of infiltrating CD4…”

Evidence of an oncogenic role of aberrant TOX activation in cutaneous T-cell lymphoma

“…Although the etiology of CTCL is not yet clear, accumulating evidence indicates that defects in apoptosis and cell cycle control are critical in disease pathogenesis. [5][6][7][8] However, the molecular events leading to these abnormalities have not been well understood. By transcriptome analysis, we have recently demonstrated that the transcript levels of thymocyte selection-associated high-mobility group (HMG) box gene (TOX) are abnormally increased in early-stage MF skin biopsy specimens but not in the biopsy specimens of benign inflammatory dermatoses (BID) or normal skin.…”