Almost all patients of Neurofibromatosis Type I (NF1) develop benign peripheral nerve tumors called neurofibromas, which are derived from neural crest Schwann cell lineage progenitors with biallelic NF1 gene mutations. More than 90% of NF1 patients develop dermal neurofibromas (DN), and 25–50% develop plexiform neurofibromas (PN). In 8–13% of individuals with NF1, PN can transform into malignant peripheral nerve sheath tumors (MPNSTs), a type of nerve soft tissue sarcoma that is the main cause of mortality of NF1 patients. In addition to arising from benign neurofibromas (50%), MPNSTs can also occur spontaneously (~40%) or following radiation therapy (~10%). Treatment for MPNST is limited to complete resection with negative margins. Still, the high recurrence of MPNST is a major concern. However, full resection of the pre-malignant lesions can largely reduce the recurrence and mortality of patients. So, early diagnosis and distinguishing malignancy from benign and premalignant lesions are particularly important. During the progression from benign neurofibromas to malignancy, a variety of changes including tumor morphology, genetic mutations, expression of multiple signaling pathways-related proteins and genome instability gradually occur. In this review, we detail these changes with the goals of identifying the histological and/or molecular signs of malignancy initiation, and an optimal therapeutic intervention window, to inhibit tumor progression and reduce the rate of mortality.

In neurofibromatosis type 1 (NF1), loss-of-function mutations in the NF1 gene increase activation of the RAS–MEK–ERK signaling cascade, driving tumorigenesis. MEK inhibitors (MEKi) inhibit tumor growth and significantly shrink nerve tumors (neurofibromas). However, MEKi treatment alone fails to eradicate tumor cells, and tumor regrowth occurs after drug withdrawal, highlighting the limitations of targeting the single MEK pathway. An alternative strategy is to promote dephosphorylation of hyperactive kinases that drive tumor growth by enhancing phosphatase activity. We identified deregulated expression of genes encoding subunits of the PP2A phosphatase in neurofibroma and neurofibroma Schwann cells. We confirmed significant reductions in both the expression and enzymatic activity of the PP2A A and C subunits. FTY720, a compound known to restore PP2A phosphatase activity, inhibited tumor sphere formation by mouse and human neurofibroma Schwann cell progenitor cells, suppressed the proliferation of both primary and immortalized neurofibroma-derived Schwann cells, and induced cell apoptosis in vitro. Furthermore, treatment with FTY720—alone or in combination with MEKi—significantly suppressed tumor number and reduced tumor burden in remaining tumors in a murine model of NF1, highlighting the promise of using FTY720 as a novel therapeutic strategy in NF1.