Mycosis Fungoides and Sézary Syndrome: An Integrative Review of the Pathophysiology, Molecular Drivers, and Targeted Therapy

Abstract

Primary cutaneous T-cell lymphomas (CTCLs) constitute a heterogeneous group of diseases that affect the skin. Mycosis fungoides (MF) and Sézary syndrome (SS) account for the majority of these lesions and have recently been the focus of extensive translational research. This review describes and discusses the main pathobiological manifestations of MF/SS, the molecular and clinical features currently used for diagnosis and staging, and the different therapies already approved or under development. Furthermore, we highlight and discuss the main findings illuminating key molecular mechanisms that can act as drivers for the development and progression of MF/SS. These seem to make up an orchestrated constellation of genomic and environmental alterations generated around deregulated T-cell receptor (TCR)/phospholipase C, gamma 1, (PLCG1) and Janus kinase/ signal transducer and activator of transcription (JAK/STAT) activities that do indeed provide us with novel opportunities for diagnosis and therapy.

Keywords: CTCL; Sézary syndrome; diagnosis; molecular drivers; mycosis fungoides; therapy.

Figure 1

Malignant network of signaling mechanisms driving MF/SS. Malignant T-cell signaling pathways frequently deregulated in MF/SS cases that can drive the pathogenesis and progression of the disease and its potential targeted inhibitors. TCR/PLCγ1–NFAT/AP-1: upon stimulation with the antigen (a), TCR activates PLCγ1, which catalyzes the formation of IP3 and DAG. IP3 promotes Ca²⁺ release, which activates calmodulin (CaM), which, in turn, activates calcineurin (CaN). CaN dephosphorylates and activates the transcription factor NFAT, which can associate with the transcription factor complex AP-1 to induce gene expression. DAG activates PKCs (including PKCθ), which, in turn, induces the activation of MAPKs (and the AP-1 complex) and NF-κB signaling pathways. CCR4/CCR7-MAPKs/NF-κB: CCL17/22 and CCL19/21 activate CCR4 and CCR7, respectively, which can trigger the activation of downstream effectors such as MAPK–ERK, mediating gene transcription via AP-1 and NF-κB, and RhoA, which regulates cytoskeletal dynamics. TNFR–NF-κB: NF-κB can also be activated downstream of membrane receptors such as TNFR. IL-R/JAK–STAT: JAK–STAT signaling pathway can be activated downstream of transmembrane receptors such as interleukin receptors. JAK kinases are constitutively associated with the intracellular tails of the receptor. Upon activation of the receptor, JAKs are tyrosine-phosphorylated, making them catalytically active and capable of recruiting members of the STAT family and phosphorylating them at tyrosine residues. Upon phosphorylation, STATs form dimers that translocate to the nucleus, where they act as transcription factors for inducing gene expression. All of these pathways converge in inducing the expression of genes involved in the pathophysiology of malignant T-cells, such as IL-2, IL-4, L-17, FOXP3, GATA3, and CCR4. Created with BioRender.com (accessed on 18 November 2020).