Transcriptomic changes during stage progression of mycosis fungoides: from translational analyses to their potential clinical implications
Authors: G. Dobos, C. Assaf
Journal: British Journal of Dermatology (2021)

Linked Article: Xiao et al. Br J Dermatol 2022; 186:520–531. Mycosis fungoides (MF) is the most frequent cutaneous T-cell lymphoma (CTCL). Early stages of the disease are characterized by eczema-like patches and often respond well to skin-directed treatments. However, approximately 25% of cases of early-stage MF may progress to a higher stage, characterized by recurrent infections and high mortality.1 In recent years, gene-sequencing-based approaches have greatly contributed to our understanding of the mutational landscape of CTCL, revealing the emergence of numerous subclones and complex patterns of clonal mutations.2 Alterations have been described in gene expression of key players of DNA damage (TP53, ATM), chromatin regulation (TOX, TWIST1), the Janus kinase/signal transducer and activator of transcription pathway (JAK3, STAT3, STAT4), T-cell-receptor and cytokine signalling (CCR4, ZEB1), the nuclear factor-κB family (NFKB2, TNFRSF1B), phosphoinositide 3-kinase/protein kinase B signalling (CDKN2A, PTEN) and cell migration (PLS3, DNM3).2 Most of these studies were based on leukaemic CTCL, usually from Sézary syndrome (SS) due to its easy accessible tumour cells from peripheral blood.2-6 However, studies over the past decade have shown clearly that MF and SS are different diseases within the group of CTCL.3 In this issue of the BJD, Xiao et al.7 describe the mutational landscape of the lymphocytic infiltrate of MF by comparing early-stage plaques against late-stage plaques and tumours from the same patients. To focus on the specific genetic imprint of the MF tumour cells, they elegantly used laser-assisted skin microdissection. This permits a higher resolution of RNA expression of malignant lymphocytes, by excluding other components such as stromal cells from the analysis. The highly tumour-enriched RNA was then analysed by both whole-transcriptome and whole-exome sequencing. As a result, the authors confirm8 and describe novel upregulated signalling pathways in advanced MF lesions, for example meiomitosis, cell survival and proliferation, and DNA repair. Moreover, during progression they found overexpression of selected genes of pathways such as mitogen-activated protein kinase kinase/extracellular signal-regulated kinase, Akt and mammalian target of rapamycin, which decipher key elements of tumour progression in MF and beyond this are of potential therapeutical value. Furthermore, they found a high transcriptional similarity of malignant cells of tumoral lesions and late-stage plaques in MF. Based on the remarkable similarities of these different skin lesions at the level of the transcriptome, they interpret this as tumour cell percolation between these anatomically distant lesions via haematogenous self-seeding. These results presented by Xiao et al. are significant because they highlight differences in the gene expression profile during the course of the disease. They also identify several candidate genes that broaden our understanding of tumour progression in CTCL. Furthermore, these findings may be exploited in further clinical trials with stratification of patients based on their specific genetic aberration, leading to personalized medicine. Finally, a key finding of the authors is the high transcriptional similarity between the late-stage plaques and tumoral lesions, which is evidence of the common origin of these lesions. This leads to the hypothesis of percolation of the malignant cells and the clinical implication of the need for early eradication of emerging tumours, for example by radiotherapy. Although the precise mechanism of tumour percolation remains open, this hypothesis may be clinically supported by the work of O'Malley et al., who demonstrated that radiotherapy eradicates malignant T cells in MF, which is associated with improved survival in early-stage disease.9 In conclusion, the work of Xiao et al. broadens our understanding of tumour progression in MF and serves as a valuable basis for further investigations regarding the role of tumour percolation and its clinical impact. Open Access funding enabled and organized by Projekt DEAL. Gabor Dobos: Conceptualization (equal); Formal analysis (equal); Writing-original draft (equal); Writing-review & editing (equal). Chalid Assaf: Conceptualization (equal); Supervision (equal); Writing-original draft (equal); Writing-review & editing (equal).