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Mechanistic evaluation of NSD3 in the pathogenesis of acute myeloid leukemia

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dc.contributor.advisor Vakoc, Christopher R. en_US
dc.contributor.advisor Mills, Alea A. en_US
dc.contributor.author Shen, Chen en_US
dc.contributor.other Department of Molecular and Cellular Biology en_US
dc.date.accessioned 2017-09-20T16:50:21Z
dc.date.available 2017-09-20T16:50:21Z
dc.date.issued 2016-12-01 en_US
dc.identifier.uri http://hdl.handle.net/11401/76473 en_US
dc.description 199 pg. en_US
dc.description.abstract The bromodomain and extra-terminal (BET) protein BRD4 is a validated drug target in hematological malignancies, owing to its essential role in sustaining oncogenic transcriptional programs. To gain insight into the cancer-relevant mechanistic function of BRD4, I have investigated its mechanism of transcriptional activation in the MLL-fusion subtype of acute myeloid leukemia (AML) with experimental approaches including small hairpin RNA (shRNA) knockdown, clustered regularly-interspaced short palindromic repeats (CRISPR)-Cas9 knockout, biochemistry, RNA sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq). In this study, I demonstrate that the AML maintenance function of BRD4 requires its interaction with NSD3, which belongs to a subfamily of H3K36 methyltransferases. Unexpectedly, AML cells were found to only require a short isoform of NSD3 that lacks the methyltransferase domain. I show that NSD3-short is an adaptor protein that sustains leukemia by linking BRD4 to the CHD8 chromatin remodeler, by utilizing a Pro-Trp-Trp-Pro (PWWP) module, and by employing an acidic transactivation domain. Phenotypic and transcriptional effects of genetic targeting of NSD3 or CHD8 mimic the effects of BRD4 inhibition. Furthermore, BRD4, NSD3, and CHD8 colocalize across the AML genome and are each released from super-enhancer regions upon chemical inhibition of BET bromodomains. These findings suggest that BET inhibitors exert therapeutic effects in leukemia by evicting BRD4-NSD3-CHD8 complexes from chromatin to suppress transcription. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Biology -- Molecular biology -- Genetics en_US
dc.subject.other cancer, epigenetics, leukemia, transcriptional regulation en_US
dc.title Mechanistic evaluation of NSD3 in the pathogenesis of acute myeloid leukemia en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Krainer, Adrian R. en_US
dc.contributor.committeemember Trotman, Lloyd C. en_US
dc.contributor.committeemember Luk, Ed en_US
dc.contributor.committeemember Hammell, Christopher M. en_US

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