Cdkn2a loss in a model of neurofibroma demonstrates stepwise tumor progression to atypical neurofibroma and MPNST

Plexiform neurofibromas (PN) are benign nerve sheath Schwann cell tumors, common in patients with neurofibromatosis type 1 (NF1), that are characterized by biallelic mutations in the NF1 tumor suppressor gene. Atypical neurofibromas (ANF) show additional frequent loss of CDKN2A/Ink4a/Arf and may be precursor lesions of aggressive malignant peripheral nerve sheath tumors (MPNST). We combined loss of Nf1 in developing Overall design: Schwann cells with global Ink4a/Arf loss and identified paraspinal PN and ANF. Confirming susceptibility to transformation, upon transplantation the ANF generated GEM-PNST similar to human MPNSTs, and tumors showed reduced p16INK4a protein and reduced senescence markers. Superficial GEM-PNST contained regions of nerve-associated PN or ANF and grew rapidly on transplantation. Transcriptome analyses showed similarities to corresponding human tumors. Thus, we recapitulate nerve tumor progression in NF1 and provide preclinical platforms for testing therapies at each tumor grade. The results support a tumor progression model in which NF1 loss in Schwann cells drives PN formation, additional Ink4a/Arf loss contributes to ANF formation, and further changes underlie transformation to MPNST.