Locus-selective targeting of the oncogenic fusion EWSR1-FLI1 in Ewing sarcoma by CRISPR/dCas9 epigenetic silencers

Shahama Taifour

Research output: ThesisDoctoral Thesis

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Abstract

Ewing sarcoma (EWS) is a highly aggressive pediatric malignancy arising mainly from bones. Chromosomal rearrangements are the key pathognomonic driver mutations in EWS. The EWSR1–FLI1 translocation produces EWS-FLI1 oncoprotein that drives 85% of EWS cases. The objective of this PhD was to implement CRISPR/dCas9-KRAB to suppress the expression of EWSR1–FLI1. The results revealed that CRISPR/dCas9-KRAB delivered by lentiviruses potently silenced the expression of EWSR1–FLI1 in vitro and in vivo. The findings demonstrated highly efficient intracellular delivery of CRISPR/dCas9-KRAB ribonucleoprotein loaded in polymeric nanoparticles, which resulted in the silencing of EWSR1–FLI1 in mouse models of EWS accompanied by potent anti-tumour effects.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • The University of Western Australia
Supervisors/Advisors
  • Blancafort, Pilar, Supervisor
  • Gaudieri, Silvana, Supervisor
  • Evans, Cameron, Supervisor
Thesis sponsors
Award date12 Jun 2024
DOIs
Publication statusUnpublished - 2024

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