Role of RNA-Exosome in PRC2- and NF1-Mutant Malignant Peripheral Nerve Sheath Tumors
Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive malignancies with a significant propensity for local recurrence and metastatic spread. Earlier studies that have characterized the genetic landscape of MPNST have shown that more than 70 percent of the cases have inactivation of polycomb repressor complex 2 (PRC2) components (SUZ12 and EED loss) in addition to NF1 loss. The rationale for the proposed research is that how loss of H3K27me3-based silencing in PRC2-mutant MPNST tissues leads to increased RNA synthesis from generally repressed regions that needs to be resolved with enhanced activity of RNA exosome components. The objective of this project is to characterize the dependency of PRC2-mutant and NF1-mutant MPNSTs on RNA-exosome components and determine how depletion of RNA-exosomes leads to accumulation of these toxic RNAs and DNA damage signaling eventually causing cell death and whether this process is aided by mistargeted EZH2in the absence of functional PRC2 complex. This proposed study will uncover novel biological insights into how RNA transcription and surveillance processes become aberrant in NF-1 and PRC2-mutant MPNSTs. This work will also determine whether inhibiting RNA exosome could be a target in cancer therapeutics.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2022
- Accession Number
- AD1190552
Entities
People
- Kunal Rai
Organizations
- The University of Texas MD Anderson Cancer Center