Abstract
Simple SummaryTransformed mycosis fungoides (LCT-MF) is a histopathological marker of poor prognosis and associated with worse survival. We compared miRNA and mRNA expression profiles of LCT-MF with classic MF and found a distinct miRNA regulatory network modulated immunosuppressive tumor microenvironment in LCT-MF. Our findings provide novel insights and therapeutic targets for LCT-MF.Large cell transformation of mycosis fungoides (LCT-MF) occurs in 20–50% of advanced MF and is generally associated with poor response and dismal prognosis. Although different mechanisms have been proposed to explain the pathogenesis, little is known about the role of microRNAs (miRs) in transcriptional regulation of LCT-MF. Here, we investigated the miR and mRNA expression profile in lesional skin samples of patients with LCT-MF and non-LCT MF using RNA-seq analysis. We found miR-146a and miR-21 to be significantly upregulated, and miR-708 the most significantly downregulated miR in LCT-MF. Integration of miR and mRNA expression profiles revealed the miR-regulated networks in LCT-MF. Ingenuity pathway analysis (IPA) demonstrated the involvement of genes for ICOS-ICOSL, PD1-PDL1, NF-κB, E2F transcription, and molecular mechanisms of cancer signaling pathways. Quantitative real time (qRT)-PCR results of target genes were consistent with the RNA-seq data. We further identified the immunosuppressive tumor microenvironment (TME) in LCT-MF. Moreover, our data indicated that miR-146a, -21 and -708 are associated with the immunosuppressive TME in LCT-MF. Collectively, our results suggest that the key LCT-MF associated miRs and their regulated networks may provide insights into its pathogenesis and identify promising targets for novel therapeutic strategies.
Highlights
Cutaneous T cell lymphoma (CTCL) is a disfiguring, incurable malignancy with a poor prognosis for those with advanced stage disease
Clinical stage is an important determinant of risk for disease progression (RDP)
Among non-Large cell transformation (LCT) patients, approximately 50% of patients had early-stage disease (IA–IB), and 50% had advanced stage disease (IIB, IVA), whereas 73% of Large cell transformation of mycosis fungoides (LCT-Mycosis fungoides (MF)) patients were diagnosed with advanced stages (IIB, IVA)
Summary
Cutaneous T cell lymphoma (CTCL) is a disfiguring, incurable malignancy with a poor prognosis for those with advanced stage disease. Mycosis fungoides (MF) is the most common primary CTCL and is characterized by expansion of malignant T-cells in a chronic inflammatory environment in the skin [1]. Patients with early-stage disease have a 10-year survival ranging between 64–98%, whereas patients with advanced stage disease have a less favorable prognosis, with a 10-year survival of. Several efforts have been made to identify biomarkers of transformation that could help prompt an early and targeted treatment to lead to a more favorable clinical outcome Large cell transformation (LCT) of CTCL, histopathologically defined by sheets or microscopic nodules of atypical T cells with a large cell phenotype four times larger than normal lymphocytes that make up at least 25% of the dermal infiltrate, is associated with rapidly progressing disease and dismal prognosis and confers a median survival of 1–4 years after transformation, which is not overcome by any regimen to date [4,5,6].
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