Understanding misbalanced signalling by JAK2-V617F in myloproliferative neoplasms fusing qualitative and quantitative modelling

The interdisciplinary research project JAK-Sys addresses the understanding of the complex signalling and influencing factors as well as the identification of therapeutic targets for myeloproliferative neoplasm (MPN). MPNs are a group of diseases of the bone marrow, in which most of the haematopoiesis occurs. The activating JAK2-V617F mutation is found in the majority of myeloid disorders [1,2], which constitutes that it and its specific signalling pathways (see image above) are attractive therapeutic targets. On the other hand JAK2 signalling is not only a factor for neoplastic cells, but also necessary for the normal haematopoiesis. Hence the complete eradication of the malignant clone is no therapeutic option. Currently only limited knowledge about the underlying molecular mechanisms as well as the resulting misregulations associated with JAK2-V617F expression exist. However, pure biological deduction and experiments are not sufficient to infer and understand the interplay of the involved factors due to the inherent complexity and the mixture of quantitative and qualitative biological and experimental information. The key methodology of this project is therefore to use combined quantitative and qualitative systems biology modelling approaches together with model-driven biological experiments. With this novel approach we aim

• to investigate the dynamics and to elucidate mechanisms of JAK2-V617F-dependent deregulated signalling as it appears in myeloproliferative neoplasms, and
• to rationally identify suitable intervention strategies for therapeutic targeting of myeloproliferative neoplasms.
Experimental and theoretical partners will closely collaborate to make this combined approach effective for elucidating key mechanisms behind aberrant JAK2 signalling and finally to predict the potential efficiency of intervention strategies to combat JAK2-V617F mediated myeloproliferative neoplasms.