Cancer, particularly acute myeloid leukaemia (AML), is aggressive and also resistant to anti-cancer therapy, resulting in poor patient outcomes. Understanding how genes can be switched on and off without affecting their DNA sequence is paramount for the development of new anti-cancer therapies.
AML is characterised by the abnormal proliferation of immature myeloid cells. The standard of care for AML patients has not changed for many years, and the 5-year survival rate for AML patients is still only about 30%. Therefore, there is an urgent need to develop novel therapies for AML. Accumulating scientific evidence indicates a role for epigenetic changes in cancer onset and progression, and new therapies could therefore be based on targeting the epigenetic state of AML.
“Epigenetic regulators are frequently mutated in AML and represent good drug targets,″ explains project coordinator Prof. Kristian Helin. The EU-funded NovLeuReg project, a Marie Skłodowska-Curie fellowship grant, aimed to identify novel epigenetic regulators in AML to support the development of personalised treatments in the future.
To identify epigenetic regulators and investigate the molecular mechanisms behind them, scientists performed loss-of-function forward genetics screens. They used the CRISPR interference genome editing technology to generate a library capable of targeting 1 046 genes of all the known and putative chromatin-associated proteins.
The future of epigenetics therapy
Collectively, the work by NovLeuReg alongside technological advancement provides novel knowledge in the field of malignant haematopoiesis. The identification of these new proteins that contribute to AML development and maintenance sheds new light into the process and mechanism underlying leukemogenesis and unveils novel therapeutic targets.
Overall, the reversible nature of epigenetic marks has raised optimism for the development of new therapies in leukaemia by pharmacological inhibition of chromatin-modifying enzymes. New therapies are much needed for this type of cancer that presents with high mortality rates and no unified treatment. Long-term, it will be possible to develop personalised therapies for AML patients following detailed molecular analysis of leukemic cells.
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