Epigenetic regulation of acute myeloid leukaemic stem cells

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Embargoed until 2018-04-30
Copyright: Leung, Halina
Acute myeloid leukaemia (AML) is a heterogeneous blood disease with high relapse rates. A small population of highly drug resistant leukaemic stem cells (LSC) persists after chemotherapy, causing disease relapse. This emphasises the need to develop novel LSC-targeted therapies. While increasing evidence has emerged in recent years highlighting the role of epigenetic regulators in cancer development and maintenance, knowledge in epigenetic regulation of LSC is limited. This study investigated the role of two novel histone demethylases, Jmjd1c and Jmjd5, in regulating LSC, as well as the effectiveness of currently available epigenetic agents on leukaemogenesis. This study has shown that Jmjd1c is required for AML development and maintenance. Experiments involving enforced expression of Jmjd1c in haematopoietic stem cells (HSC) suggested that Jmjd1c has the capacity to enhance stem cell proliferation. Jmjd1c overexpression also promoted proliferation of HSC transduced with oncogenes, Hoxa9/Meis1a, and accelerated leukaemia development in mice. Gene expression profiling identified Jmjd1c to be a critical regulator of metabolic pathways such as glycolysis. These novel findings support the importance of targeting Jmjd1c. This study also provided the first evidence of Jmjd5 as a potential tumour suppressor in AML. Overexpression of Jmjd5 significantly impaired LSC proliferation and prolonged mouse survival. Gene expression profiling and functional studies suggested that Jmjd5 negatively regulated a LSC self-renewal pathway driven by G protein-coupled receptor 84 (Gpr84). Given the partially shared downstream signalling of Jmjd5 and Gpr84, it is likely that Jmjd5 negatively regulates LSC function, at least in part, by inhibiting Gpr84 signalling. Jmjd1c and Jmjd5 have previously been shown to regulate histone methylation. Although global H3K9me2 levels were not altered by Jmjd1c, Jmjd5 reduced global H3K36me2 and H3K27me3 levels. Reduction in H3K27me3 could also be achieved by DZNep-induced Ezh2 inhibition at low doses, which altered the gene expression profile of DZNep-treated AML cells. In summary, both Jmjd1c and Jmjd5 were found to be crucial in the proliferation and maintenance of AML cells, suggesting that targeting aberrant methylation mediated by these epigenetic regulators may provide a promising approach in AML therapy.
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Leung, Halina
Wang, Jenny
Norris, Murray
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PhD Doctorate
UNSW Faculty
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