STAT5B as a prognostic marker of thrombosis in MPN

Myeloproliferative neoplasms (MPNs) are a group of blood cancers that can occur when blood stem cells acquire specific DNA mutations. These mutations lead to an abnormal expansion of mature blood cells, such as red blood cells, white blood cells or large cells called megakaryocytes (MKs). MKs are responsible for producing small fragments called platelets, which facilitate blood-clotting, and abnormal MKs play an important role in the pathogenesis of MPNs. The most common mutation found in up to 95% of MPN patients occurs in the JAK2 protein, and this in turn causes increased and unregulated activation of the STAT5B protein, which promotes cell survival and growth. The main cause of death in MPN patients is fatal blood- clotting events (thromboembolisms), and both MKs and the presence of the JAK2 mutation are associated with thrombosis development. However, given that most MPN patients have abnormal MKs as well as a JAK2 mutation, additional markers are still needed to identify patients at high or low risk of thromboembolism. There are also sex-specific differences in MPN; men have worse disease progression whereas women have more MK cell expansion and higher rates of venous thrombosis. The molecular reasons for these sex-based differences are also unknown. We have found that increased STAT5B levels in MPN patients with mutated JAK2 are associated with patients developing thromboembolisms. Based on these findings, we generated a mouse model that develops MPN and has increased STAT5B levels, and we find that different STAT5B levels affect disease severity and the potential for MK cell expansion. We also observe striking sex-specific differences in our mouse data, closely resembling human disease. In this project, we will use our novel mouse model, mouse and human MPN cell systems as well as MPN patient data to understand the role of the STAT5B protein in MPN disease prognosis and thrombosis risk. We will use next-generation sequencing technologies to reveal the molecular functions of STAT5B in MPN cells and how increased STAT5B levels can drive the observed disease phenotypes. Additionally, studying our MPN mouse model will allow us to dissect the impact of STAT5B on MK cell and platelet expansion as well as assess the rate of thrombosis development in a physiological setting. Lastly, we will also use these approaches to assess how increased STAT5B levels differently affect males and females with MPN, uncovering the molecular mechanisms causing these sex- specific differences. From this project, we expect to reveal the potential of using STAT5B levels as a new prognostic marker for predicting risk of fatal blood clots and disease outcome in MPN. Our study could also have potential broad relevance for thrombotic disease and mechanisms behind sex-specific differences in other blood cancers.