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dc.contributor.authorAdam, Deveau
dc.date.accessioned2016-01-14T18:03:42Z
dc.date.available2016-01-14T18:03:42Z
dc.identifier.urihttp://hdl.handle.net/10222/65298
dc.description.abstractAcute myeloid leukemia (AML) is a genetic disease whereby sequential genetic aberrations alter essential white blood cell development leading to differentiation arrest and hyperproliferation. Pertinent animal models serve as essential intermediaries between in vitro molecular studies and the use of new agents in clinical trials. We previously generated a transgenic zebrafish model expressing human NUP98-HOXA9 (NHA9), a fusion oncogene found in high-risk AML. This expression yields a pre-leukemic state in both embryos and adults. Using this model, we have identified the overexpression of dnmt1 and the Wnt/β-catenin pathway as downstream contributors to the myeloproliferative phenotype. Targeted dnmt1 morpholino knockdown and pharmacological inhibition with methyltransferase inhibitors rescues NHA9 embryos. Similarly, inhibition of β-catenin with COX inhibitors partially restores normal hematopoiesis. Interestingly, concurrent treatment with a histone deacetylase inhibitor and either a methyltransferase inhibitor or a COX inhibitor, synergistically inhibits the effects of NHA9 on embryonic hematopoiesis. Thus, we have identified potential pharmacological targets in NHA9-induced myeloid disease that may offer a highly efficient therapy with limited toxicity – addressing a major long-term goal of AML research.en_US
dc.language.isoenen_US
dc.subjectacute myeloid leukemiaen_US
dc.subjectDecitabineen_US
dc.subjectdnmt1en_US
dc.subjectepigeneticsen_US
dc.subjectValproic Aciden_US
dc.subjectWnt/Beta-Cateninen_US
dc.titleUSING A TRANSGENIC ZEBRAFISH MODEL TO IDENTIFY DOWNSTREAM THERAPEUTIC TARGETS IN HIGH-RISK, NUP98-HOXA9-INDUCED MYELOID DISEASEen_US
dc.typeThesis
dc.date.defence2013-07-25
dc.contributor.departmentDepartment of Microbiology & Immunologyen_US
dc.contributor.degreeMaster of Scienceen_US
dc.contributor.external-examinerDr. Wenda Greeren_US
dc.contributor.graduate-coordinatorDr. Brent Johnstonen_US
dc.contributor.thesis-readerDr Jason Bermanen_US
dc.contributor.thesis-readerDr. Brent Johnstonen_US
dc.contributor.thesis-readerDr. Rob Liwskien_US
dc.contributor.thesis-supervisorDr. Jason Bermanen_US
dc.contributor.ethics-approvalReceiveden_US
dc.contributor.manuscriptsNot Applicableen_US
dc.contributor.copyright-releaseNot Applicableen_US
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