DLK1 Distinguishes Subsets of NF1-Associated Malignant Peripheral Nerve Sheath Tumors with Divergent Molecular Signatures

We aimed to investigate the molecular mechanisms underlying the malignant transformation of pre-existing neurofibromas (PNST) to malignant peripheral nerve sheath tumors (MPNST) in individuals with neurofibromatosis type 1 (NF1). Our primary focus was on the role of DLK1 in this transformation process and its potential as a biomarker for diagnosis, risk assessment, and therapeutic stratification. This study consisted of a case set of peripheral nerve sheath tumor specimens, including plexiform neurofibromas, atypical neurofibromas, and MPNSTs, acquired under IRB approval at our institution. The majority of the subjects had neurofibromatosis type 1. The study found that DLK1 is significantly increased in MPNST compared to non-malignant neurofibromas. DLK1 overexpression may precede histological changes indicative of malignancy. Higher serum levels of DLK1 were observed in both mice and humans with MPNST. Divergent levels of DLK1 expression identified distinct MPNST subsets with unique molecular characteristics and potential therapeutic targets. Overexpression of DLK1 was associated with the reactivation of embryonic signatures, an immunosuppressive microenvironment, and poorer overall survival in NF1-MPNST patients.