The role of additional mutations in treatment response and disease progression in MPN

Can be adapted in scope for Honours, Masters or PhD project

MPNs are a group of disorders characterised by the excess production of mature myeloid cells. MPNs are driven by the constitutive activation of the JAK-STAT signalling pathway as a consequence of mutations in either JAK2, MPL or CALR in haematopoietic stem cells (HSC). Pioneering work from our laboratory has demonstrated the efficacy of interferon alpha (IFNα) in the preferential targeting of MPN stem cells. In addition to these MPN-driver mutations, patients often present with additional mutations that can alter disease presentation. It is currently unclear if and how the presence of additional mutations may alter treatment outcomes in MPN, particularly in response to IFNa, and what mutation combinations are sufficient to drive transformation to leukaemia.

In this project we will use our well-established murine model of mutant Jak2-driven MPN in combination with CRISPR engineering technology to generate additional mutation combinations observed in the human disease. By treating these genetically engineered mice with IFNα we will determine what additional mutations or mutation combinations confer resistance to therapy and how. By ageing these mice and monitoring their disease phenotype long-term we will determine what mutation combinations result in the emergence of leukaemia. These studies will primarily employ mouse procedural work, primary cell culture, flow cytometry and basic molecular biology. Mechanistic studies are likely to include the use of high content sequencing technologies like RNAseq and ATACseq at a bulk, and possibly single cell level.