Loss of Schwann cell's normal rhythmic core clock gene expression and gain of rhythmic expression of oncogenic driver genes in malignant NF1-associated peripheral nerve sheath tumor

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor syndrome caused by pathogenic variants in the NF1 gene. Beside tumor formation, patients often have sleep disturbances, suggesting circadian involvement. Previous NF1 studies have implicated MAPK pathway, cAMP-PKA, calcium signaling, and ALK in circadian regulation, and shown disrupted rhythms in murine astrocytes lacking NF1. However, whether human Schwann cells show rhythmic gene expression remains unknown, although impaired rhythms may contribute to tumorigenesis. In this study, we analyzed normal human Schwann cells and NF1-derived malignant peripheral nerve sheath tumors (MPNST) for rhythmic gene expression. Cultured cells were synchronized via serum shock, and mRNA levels of core clock and associated genes (e.g. ARNTL, JUN, TGFA, CLOCK, VEGFA, MYC) were quantified at defined intervals. We observed rhythmic core clock gene expression in normal Schwann cells, demonstrating intrinsic circadian oscillations in peripheral glia. In contrast, MPNST lacked rhythmicity in core clock genes, instead showing de novo rhythmic expression of oncogenes and growth factors like MYC and VEGFA. Thus, loss of clock gene rhythmicity (desynchronization) and emergence of rhythmic oncogene expression (synchronization) in NF1-associated MPNST further our understanding of peripheral glial physiology and tumorigenesis. These insights suggest that chronotherapeutic strategies may be beneficial for NF1-associated MPNST.