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    Identification of KIT as a Suppressor of BRAFV600E-Mutant Melanoma

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    Authors
    Neiswender, James V.
    Faculty Advisor
    Craig J. Ceol
    Academic Program
    Cancer Biology
    UMass Chan Affiliations
    Program in Molecular Medicine
    Document Type
    Doctoral Dissertation
    Publication Date
    2017-11-09
    Keywords
    Zebrafish
    Melanoma
    KIT
    BRAFV600E
    MAPK
    Biology
    Cancer Biology
    Genetics
    
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    Abstract
    Genetic changes acquired in the pigment producing cells of the skin, called melanocytes, can lead to formation of the deadly cancer melanoma. Mutations or amplifications leading to the activation of the RAS/MAPK pathway occur in more than 90% of melanomas. Melanocyte development and survival requires the stimulation of this pathway by the receptor tyrosine kinase (RTK) KIT. In ~2% of melanomas, oncogenic KIT mutations drive tumor formation; however, the majority of melanomas lose wild-type KIT expression, suggesting that KIT could suppress melanoma formation. In human melanoma patients of The Cancer Genome Atlas (TCGA), we found an association between BRAFV600E mutations and low KIT mRNA expression, so we tested whether KIT loss would affect BRAFV600E-driven tumor onset by crossing a kit(lf) mutant allele into melanoma-prone Tg(mitfa:BRAFV600E); p53(lf) zebrafish. We observed that kit(lf)-mutant zebrafish experienced accelerated tumor onset and their tumors had increased RAS/MAPK pathway activation. In BRAFV600E-mutant melanoma cells, KIT activity reduced RAS/MAPK signaling by promoting activation of wild-type BRAF (BRAFWT). Furthermore, we found that overexpression of BRAFWT delayed tumor onset in Tg(mitfa:BRAFV600E); p53(lf); mitfa(lf) zebrafish, but had no effect in kit(lf); Tg(mitfa:BRAFV600E); p53(lf); mtifa(lf) zebrafish and a cohort of TCGA BRAFV600E-mutant melanoma patients with high KIT expression and high BRAFWT allele ratios experienced a reduced likelihood of metastasis and extended overall survival. These studies indicate that wild-type KIT acts to suppress melanoma formation through activation of BRAFWT, causing reduced signaling output of BRAFV600E-mutant cells.
    DOI
    10.13028/M27Q3P
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/32311
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/M27Q3P
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