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Dissertation/Thesis Abstract

Genetic and Epigenetic Regulation of Cell Signaling Guides the Clinical Progression of NF1-Related Neurofibromas
by Grit, Jamie Lynn, Ph.D., Van Andel Research Institute, 2021, 195; 28317822
Abstract (Summary)

Neurofibromatosis Type 1 (NF1) is a tumor predisposition syndrome caused by inactivating mutations in the NF1 gene. Nearly all NF1 patients develop benign peripheral nerve tumors called neurofibromas, which have limited treatment options and are a major cause of morbidity. Additionally, some neurofibroma subtypes have the potential to transform into malignant peripheral nerve sheath tumors (MPNSTs), which are the leading cause of death in NF1 patients. Broadly, the objective of this work was to characterize the molecular mechanisms that contribute to the morbidity and mortality associated with benign neurofibromas and MPNSTs with the goal of identifying novel therapeutic targets. We profiled the DNA methylation landscape of patient tumor samples and found that benign neurofibromas that are prone to pain, itch, and burning are associated with epigenetic reinforcement of p38 activation and inflammatory pain signaling. With regards to MPNSTs, we evaluated the role of different genetic drivers in chemotherapy and targeted therapy response, as treatment resistance is a significant clinical issue. Proteomic analysis of MPNST mouse models revealed that Met amplification induces oncogene addiction and MET inhibitor sensitivity, while Trp53 loss plays a dynamic role in drug response, in part through a novel role of p53 in regulating cell signaling. Collectively, these studies identified targetable changes in kinase signaling that regulate diverse aspects of benign and malignant neurofibroma disease manifestation.

Indexing (document details)
Advisor: Steensma, Matt
Commitee: Graveel, Carrie, Grohar, Patrick , Williams, Bart, Gutmann, David
School: Van Andel Research Institute
Department: Biomedical
School Location: United States -- Michigan
Source: DAI-B 82/8(E), Dissertation Abstracts International
Subjects: Cellular biology, Genetics, Molecular biology
Keywords: Cell signaling, Neurofibromas, Genetic regulation, Epigenetic regulation
Publication Number: 28317822
ISBN: 9798582502609
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