Classical myeloid proliferative neoplasms (MPN) arise from mutations in haematopoietic stem cells that drive the constitutive activation of JAK-STAT signalling, the most common of these being JAK2V617F. Disease progression to secondary AML (sAML) is frequently associated with the acquisition of additional genetic lesions. Secondary AML is largely refractory to standard of care chemotherapy and confers a dismal prognosis. A greater understanding of the molecular events involved in the transformation of MPNs is essential for identifying and optimising treatment options in this difficult subset of AML.
We used a genetically engineered murine knock-in model of Jak2V617F MPN to determine the mechanistic basis of the MPN stem-cell targeted therapy pegylated interferon alpha (pegIFNa). We have used these findings to identify the unique vulnerabilities of Jak2V617F over wildtype stem cells in order to enhance the therapeutic window of pegIFNa through novel treatment combinations. We have also developed a CRISPR-based model of Jak2V617F MPN disease progression to sAML through Trp53-loss. We are using this model to determine if the loss of Trp53 alters haematological or molecular responses of Jak2V617F MPN to pegIFNa and if chronic pegIFNa administration is capable of either delaying or accelerating disease progression to sAML. To complement these murine studies we have developed a single-cell sequencing pipeline that allows us to resolve the cellular complexity of the HSPC compartment in the bone marrow of MPN and sAML patients at the transcriptional level and determine how this is altered by the presence of both MPN-driver and additional MPN-associated mutations.