Targeting the Core Transcriptional Regulatory Circuitry in Treating MPNSTs
Abstract
Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder that affects ~1/3500 newborns with a germline mutation in tumor suppressor gene NF1. A life-threatening complication of having NF1 is the development of an aggressive and highly metastatic malignant peripheral nerve sheath tumor (MPNST) at an earlier age compared to the general population. Currently, there are no effective treatments for MPNST other than complete surgical resection with wide margins. Patients with NF1 develop MPNSTs through the malignant transformation that is accompanied by a genetic model: 1) About 50% of NF1 patients exhibit plexiform neurofibromas, which are caused by the loss-of-function in NF1 and the associated hyper activated Ras signaling pathway, 2) Atypical neurofibromas arise from PNs and they exhibit loss of CDKN2A, and 3) approximately 13% of NF1 patients develop MPNSTs, in which recurrent mutations in SUZ12 and/or EED, two key components of the polycomb repressive complex 2 (PRC2), were identified, leading to loss of tri-methylation of histone H3 lysine 27 (H3K27me3) in these tumors. PRC2 and its product H3K27me3 are critical epigenetic modifiers contributing to the maintenance of transcriptional repression of essential genes for normal cellular function. To explore the epigenetic changes following PRC2 loss, I profiled the epigenetic landscapes in MPNSTs and found that histone marker of super enhancers, acetylated-H3K27 (H3K27ac), was gained as H3K27me3 was lost, indicating the potential impact of super enhancer-defined core transcriptional regulatory circuitry (CRC) in driving MPNST tumorigenesis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2021
- Accession Number
- AD1149983
Entities
People
- Xiyuan Zhang
Organizations
- Geneva Foundation