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Title: The role of EZH2 in the induction and maintenance of acute myeloid leukaemia
Author: Basheer, Faisal Tirupattur Mohamed
ISNI:       0000 0004 7227 1838
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2018
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Epigenetic regulators are commonly mutated in cancer. Activating mutations and overexpression of EZH2 occur in lymphoma and other malignancies, while loss-of-function mutations are found in myeloid malignancies. This thesis is a study of this apparent contradiction, examining the importance of cellular context for Ezh2 loss during the evolution of a single malignancy, Acute Myeloid Leukaemia (AML). This work demonstrates diametrically opposite functions for Ezh2 at early and late stages during the evolution of leukemias generated by disparate AML-associated fusion-oncogenes. Ezh2 functions as an oncogene that may be therapeutically targeted during disease maintenance. In contrast, Ezh2 behaves as a tumour suppressor gene during AML induction. Integrated genomic analysis demonstrates that largely different expression programmes are de-repressed during disease induction and maintenance following Ezh2 loss. Studying disease induction, Ezh2 represses a subset of bivalent promoters that resolve towards gene activation upon Ezh2 loss, inducing a feto-oncogene programme including genes like Plag1, whose overexpression phenocopies Ezh2 loss to accelerate AML induction in mouse models. This data highlights the importance of cellular context and phase of disease evolution for Ezh2 function. Moreover, the work herein identifies EZH2 as a potential target in AML, whilst providing reassurance of the safety of this therapeutic strategy.
Supervisor: Huntly, Brian J. P. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Acute Myeloid Leukaemia ; EZH2 ; Epigenetics