New insights into the neurofibroma tumor cells of origin

Abstract Neurofibromatosis type I (NF1) is a debilitating inherited tumor syndrome affecting around 1 in 3000 people. Patients present with a variety of tumors caused by biallelic loss of the tumor suppressor neurofibromin (NF1), a negative regulator of Ras signaling. While the mechanism of tumor formation is similar in the majority of NF1 cases, the clinical spectrum of tumors can vary depending on spatiotemporal loss of heterozygosity of NF1 in cells derived from the neural crest during development. The hallmark lesions that give NF1 its namesake are neurofibromas, which are benign Schwann cell tumors composed of nervous and fibrous tissue. Neurofibromas can be found in the skin (cutaneous neurofibroma) or deeper in body near nerve plexuses (plexiform neurofibroma). While neurofibromas have been known to be Schwann cell tumors for many years, the exact timing and initiating cell has remained elusive. This has led to difficulties in developing animal models and successful therapies for NF1. A culmination of recent genetic studies has finally begun to shed light on the detailed cellular origins of neurofibromatosis. In this review, we will examine the hunt for neurofibroma tumor cells of origin through a historical lens, detailing the genetic systems used to delineate the source of plexiform and cutaneous neurofibromas. Through these novel findings, we can better understand the cellular, temporal, and developmental context during tumor initiation. By leveraging this data, we hope to uncover new therapeutic targets and mechanisms to treat NF1 patients.