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Unravelling the role of protein oligomerisation in acute myeloid leukemia

54 months
Approved budget:
Dr Natalia Yewdall
Professor Renwick Dobson
Professor Mark Hampton
Health issue:
Cancer (oncology)
Proposal type:
Emerging Researcher First Grant
Lay summary
Acute myeloid leukaemia (AML) is an aggressive cancer with a 25% survival rate. Approximately 700 adults and 40 children are diagnosed with AML in New Zealand each year. Our fundamental understanding of key mechanisms behind AML remains incomplete. One key driver is mutated oligomeric proteins called nucleophosmin 1 (NPM1). NPM1 is normally found in the nucleolus of healthy cells where it is bound to ribosomal RNA (rRNA), but mutations can disrupt localisation. Here, NPM1 and AML-specific mutants will be purified and mixed with rRNA to form liquid-liquid phase separated droplets that model the nucleolus. The oligomeric states of these complexes will be characterised using biophysical techniques. Mutant proteins will be overexpressed in relevant cell lines to test their properties in situ, and help unravel the role of NPM1 oligomerisation in AML. These experimental systems will also provide a new high-throughput platform for the screening and development of novel therapies.