Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas that can arise most frequently in patients with neurofibromatosis type 1 (NF1). Despite an increasing understanding of the molecular mechanisms that underlie these tumors, there remains limited therapeutic options for this aggressive disease. One potentially critical finding is that a significant proportion of MPNSTs exhibit recurrent mutations in the genes EED or SUZ12, which are key components of the polycomb repressive complex 2 (PRC2). Tumors harboring these genetic lesions lose the marker of transcriptional repression, trimethylation of lysine residue 27 on histone H3 (H3K27me3) and have dysregulated oncogenic signaling. Given the recurrence of PRC2 alterations, intensive research efforts are now underway with a focus on detailing the epigenetic and transcriptomic consequences of PRC2 loss as well as development of novel therapeutic strategies for targeting these lesions. In this review article, we will summarize the recent findings of PRC2 in MPNST tumorigenesis, including highlighting the functions of PRC2 in normal Schwann cell development and nerve injury repair, as well as provide commentary on the potential therapeutic vulnerabilities of a PRC2 deficient tumor cell.
Highlights
Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder caused by inactivating mutations in the tumor suppressor gene NF1 and affects roughly 1/3000 newborns worldwide [1,2]
We summarize here a wide variety of human Malignant peripheral nerve sheath tumors (MPNSTs) cell lines frequently used in preclinical investigations (Table 1)
The advance of next generation sequencing (NGS) enabled the discovery of polycomb repressive complex 2 (PRC2) loss in MPNSTs, and the loss of H3K27me3 has become a clinically useful, sensitive, and specific marker for diagnosis
Summary
Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder caused by inactivating mutations in the tumor suppressor gene NF1 and affects roughly 1/3000 newborns worldwide [1,2]. In addition to the association of GOF mutations in EZH2 with notable in diffuse intrinsic pontine gliomas and pediatric non-brainstem high-grade gliomas, where oncogenesis, some studies have implicated the overexpression of this gene in cancer development mutation in histone H3 yields variant, K27M, that binds and mislocalizes PRC2 in addition to despite an absence of mutations in the coding region, such as in multiple myeloma [37,38,39], prostate, inhibiting its function [41,42] These brain tumors exhibit global loss of breast, and endometrial cancers [31,40]. Whether the PRC2 loss in MPNST cells affects the PRC1 complex and the ubiquitination of the epigenome remains to be determined but may represent a unique vulnerability and target in this disease
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