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Dissecting the Epigenetic Consequences of ATRX Mutations in Cancer
Başlık:
Dissecting the Epigenetic Consequences of ATRX Mutations in Cancer
Yazar:
Qadeer, Zulekha A., author. (orcid)0000-0002-1335-660X
ISBN:
9780438148703
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (173 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-11(E), Section: B.
Advisors: Emily Bernstein Committee members: Stuart A. Aaronson; Patrizia Casaccia; Timothy A. Chan; Matthew J. O'Connell; Martin J. Walsh.
Özet:
Mutations and structural alterations of the SWI/SNF-like chromatin remodeler ATRX have been reported at high frequency in a number of adult and pediatric tumors of neural origin. However, the consequences of ATRX mutations in cancer and their underlying epigenetic sensitivities remain ill defined. I sought to comprehend how ATRX mutations remodeled the epigenome to promote cancer progression. Particularly intriguing are the large N-terminal deletions of ATRX in neuroblastoma that generate in-frame fusion (IFF) proteins devoid of key chromatin interaction domains. Here I demonstrate that neuroblastoma cells harbouring ATRX IFFs have distinct gene expression programs compared to neuroblastoma cells that are wild type for ATRX. This is due in part to H3K27me3-mediated silencing of REST (RE1 Silencing Transcription Factor) target genes involved in neuronal differentiation. In turn, I find that ATRX IFF cells display exquisite sensitivity to EZH2 inhibition in both adherent and multicellular tumorsphere conditions, due in part to derepression of neurogenesis genes, including REST targets. Examination of the epigenomic landscape of a pediatric neuroblastoma tumor harboring an ATRX IFF revealed that H3K27me3 occupies a subset of REST target genes that are transcriptionally silenced, and sensitive to EZH2 inhibition in our cell-based assays. Thus, my study greatly advances our understanding of indolent neuroblastoma and identifies EZH2 inhibition as a potential therapy for patients with ATRX mutant disease. Moreover, I also explored the role of ATRX in melanoma and high grade gliomas. In collaboration, I reported a significant decrease in ATRX mRNA and protein levels in melanoma tissue that correlated with disease progression. This was the first study identifying ATRX loss in melanoma, independent of mutations, and proposed ATRX as a biomarker to predict disease prognosis. Additionally, I also interrogated the potential implications of ATRX mutations in high grade gliomas and found that ATRX-deficient astrocytes were more proliferative with increased neurosphere formation. These findings mimicked overexpression of mutant IDH1 protein, an alteration frequently found to co-occur with ATRX and TP53 mutations in gliomas, suggesting cooperativity. Collectively, my findings give novel insight on ATRX function in these malignancies with therapeutic implications to treat these devastating diseases.
Notlar:
School code: 1734
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(696149.1) | 696149-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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