Blood cells have a limited life-span and must be constantly replaced. Blood cell formation occurs in the bone marrow and is tightly regulated to assure that the right amount of cells is produced. During the many cell divisions needed for substituting blood cells, mutations can occur in a gene called 'Janus kinase 2' (JAK2) that result in an overproduction of red blood cells, white blood cells, and platelets. The resulting blood disease is called 'myeloproliferative neoplasm' (MPN) and can manifest as one of 3 entities called polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). This JAK2 mutation is acquired only in the blood cells and is not inherited to th...

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Blood cells have a limited life-span and must be constantly replaced. Blood cell formation occurs in the bone marrow and is tightly regulated to assure that the right amount of cells is produced. During the many cell divisions needed for substituting blood cells, mutations can occur in a gene called 'Janus kinase 2' (JAK2) that result in an overproduction of red blood cells, white blood cells, and platelets. The resulting blood disease is called 'myeloproliferative neoplasm' (MPN) and can manifest as one of 3 entities called polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). This JAK2 mutation is acquired only in the blood cells and is not inherited to the person's children. JAK2 is an enzyme that transmits signals coming from the outside into the cell and this mutation in JAK2 (JAK2-V617) amplifies the growth promoting effect of these signals so that more blood cells are formed. MPNs can progress to myelofibrosis or acute leukemia. Through the discovery of JAK2-V617 advances have been made in the diagnosis and treatment of MPN, but in many cases progression of MPN cannot be prevented and there is currently no curative treatment. Our project aims at studying very early phase of MPM when the JAK2-V617 mutation is already detectable in blood cells, but has not yet expanded to cause clinical MPN. This stage is called 'clonal hematopoiesis of indeterminate potential' (CHIP) and can be detected in up to 3% of older otherwise healthy individuals. We are examining which factors determine whether a clinical manifestation of MPN will evolve from the CHIP stage and we will explore therapeutic interventions that can prevent MPN or eradicate early stages of MPN. A second focus of our project is to understand once MPN evolved and has been diagnosed, which factor favor or inhibit the progression to myelofibrosis and acute leukemia. Understanding these processes will open new possibilities for the development of mechanism-based therapeutics.

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