Abstract
Mycosis fungoides (MF) is a low-grade cutaneous T-cell lymphoma, in which malignant T cell clones (mostly CD4+) arise in the skin from the early disease stages. IFN-α is widely used in the treatment of MF and when used in combination with PUVA has been reported as an effective treatment, with overall response rates of 30%–80%, and complete response rates of 14%–25%.
However, up to date there is no information available on prognostic factors that could help to predict response to IFN-α /PUVA in MF. The purpose of the study was to find the molecular signature associated with IFN-α /PUVA resistance, or lack of remission after IFN-α /PUVA treatment. The gene expression profile of the pre-treatment samples from 30 MF patients enrolled in a random clinical trial with IFN-α and/or PUVA has been analyzed by use of cDNA microarrays. Following the treatment outcome, the patients have been divided into good responders (23 patients that have achieved complete remission in the time of 24 weeks or less) and bad responders (7 patients that have not reached completed remission or have shown progression of the disease during treatment). The genes associated with good vs. bad response have been identified. Four genes associated with cell cycle regulation and tumour microenviroment have been identified to predict good response by the significance analysis of microarrays (SAM) correlating expression data with survival time. Moreover, 38 genes involved in T cell receptor signaling pathway, NF-kB activation and Jak-Stat signaling pathway have been found to be associated with unfavorable response to treatment by use of SAM analysis. This was validated using other bioinformatics tools based on t-statistics and Cox-model, applying False Discovery Rate for multiple testing. Furthermore, using a web-based tool (Signs) that uses a combination of gene filtering, clustering and survival model building, a 2-gene model has been obtained. This model could distinguish two groups of MF patients with probability of remission at 24 weeks of 15%, and 60% (log-rank test, p:0.007). This confirms that TCR-signaling plays a key role in cutaneous T-cell lymphoma cell survival; and could potentially be used for stratifying MF patients treated with IFN-α /PUVA into different risk-groups, if confirmed in additional studies.
Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified