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Project

The molecular pathogenesis of essential thrombocythemia: identification of novel signal transduction pathways and novel driver mutations.

Megakaryocytes are rare bone marrow cells, which produce blood platelets in a tightly regulated way. Essential thrombocythemia (ET) is a malignant blood disease, with increased platelet production, and increased risk of thrombosis, marrow failure and leukemia. The incidence is ~1/100000 persons/y. High risk patients need chemotherapy to control platelet counts and platelet inhibitors to curtail the thrombotic risk. Several acquired gene mutations, e.g. JAK2 V617F or MPL W515K/L, were discovered in the past decade, which are causative of ET. Most recently, somatic CALR mutations were found in ~25% of ET. The mechanisms by which the latter transform hematopoietic cells are still unknown. In this application, we propose strategies to explore these unknown transforming mechanisms. In ~15% of ET, the causative mutations remain unknown. It is our second major aim to discover novel driver mutations in this subgroup. We will apply massively parallel sequencing, the latest genetic technology, for the analysis of peripheral blood, bone marrow or purified megakaryocytes from patients with molecularly unexplained ET. We will trace the hematopoietic cell type in the marrow in which the founder mutations first occur. Finally, these mutations can become new diagnostic/prognostic markers, and targets for novel therapies in ET. This project may thus generate new insights in the biology and pathology of platelet production, with long-term perspectives for improved diagnosis and therapy.

Date:1 Jan 2015 →  31 Dec 2018
Keywords:Essentiële thrombocythemie
Disciplines:Laboratory medicine, Palliative care and end-of-life care, Regenerative medicine, Other basic sciences, Other health sciences, Nursing, Other paramedical sciences, Other translational sciences, Other medical and health sciences