The JAK2-V617F Mutation as a therapeutic target against Thrombosis in MPD

• Applicant: Dr. Amrei Dorothea Strehl
• Subject Area: Cardiology, Angiology
• Term: Funded in 2008
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 83596947

Patients with myeloproliferative disorders (MPD) display high platelet count in essential thrombocythemia (ET), high red blood cell mass in polycythemia vera (PV) and marrow fibrosis in primary myelofibrosis (IMF). MPD is frequently associated with bleeding, thrombosis and secondary myelofibrosis (in PV and ET) and leukemia. Thrombosis represents the most frequent cause of death in MPD and significantly affects quality of life of the patients. The discovery of a mutation in the Janus kinase 2 at position 617 (Jak2V617F) present in 54% of all patients with MPD (1-5) was a major step towards understanding the pathophysiology of the disease. To clarify the mechanism how Jak2V617F is involved in the thrombotic complications in MPD I will examine features and function of platelets from patients positive for Jak2V617F. Our previous studies (6) confirm a significant correlation of Jak2V617F mutation with the occurrence of venous thrombotic events particularly in deep venous thrombosis (Figure 1). Using specific mouse models I will also evaluate the therapeutic agents that are currently used in MPD therapy for their in vivo effect on Jak2V617F positive cells. Using a proteomic approach, it is planned to identify functionally relevant Jak2 interacting proteins in platelets and the pathways that are involved and evaluate them as potential candidates for therapeutic targets in Jak2V617F positive MPD. Short-term goal and the objectives of this proposal is to understand the basis of association of Jak2V617F with thrombosis in MPD, and analyze the role of Jak2 in platelet function. The long-term goal is to develop strategies for therapeutic intervention to reduce the thromboembolic complications in MPD, and thus, improve quality of life and survival rate of patients with MPD.

• DFG Programme: Research Fellowships
• International Connection: Austria
• Host: Dr. Robert Kralovics