MPN2AML · Identification of novel genetic regulators governing leukaemic transformation from myeloid proliferative neoplasms

As humans age, the risk of genetic aberrations increases, particularly in rare populations of blood-cell-producing haematopoietic stem cells (HSCs). Mutations in HSCs can give rise to myeloproliferative neoplasms (MPNs), which are treatable in many cases with therapies such as interferon-α (IFNα). However, 1–20% of patients progress to secondary acute myeloid leukaemia (sAML), a disease associated with poor prognosis and high mortality. This transformation is often driven by high molecular risk (HMR) mutations and is further exacerbated by pro-inflammatory cytokine environments.This proposal will address these challenges by developing novel murine models to study how specific combinations of co-occurring mutations interact to drive disease progression and transformation. Modelling will occur via a flexible genetic engineering pipeline that allows generation of multiple mutational combinations in HSCs from which MPN is initiated. Complementary profiling of cytokine networks will identify inflammatory drivers of pathology. Together, these approaches will provide mechanistic insights into the molecular and microenvironmental determinants of MPN progression to sAML.The project will be hosted by leading experts in haematological malignancies: Dr Steven Lane at QIMR Berghofer (Australia, outgoing phase) and Dr. Florian Heidel at Hannover Medical School (MHH,Germany, return phase). The applicant will bring expertise in stem cell dynamics and molecular haematology while gaining advanced skills in preclinical modelling, bioinformatics, and translational haematology.The fellowship will generate impactful publications, highly relevant to the haematological community and public, strengthen European excellence in blood cancer research, and reinforce the ERA by consolidating advanced expertise within Europe while fostering durable international collaborations.