Our group Inflammation in MPN is interested in the molecular and cellular causes of inflammation during leukemia-like diseases. Our model system are myeloic neoplasms, which are caused by mutations in the JAK2 kinase (JAK2-V617F) or the calreticulin gene. These diseases are classified as so-called myeloproliferative neoplasms (MPNs) and comprise polycythemia vera (PV), essential thrombocytosis (ET) and primary myelofibrosis (PMF). All three diseases are associated with a pronounced inflammatory reaction. Both the cause of this inflammation, as well as the effects on oncogenic myelopoiesis are not sufficiently understood. Clinically, the inflammation causes severe symptoms such as fever, cachexia and an enormous increase of the spleen (splenomegaly). The main causes of death during MPN are thrombotic events and bleedings. These in turn are induced by the inflammation together with qualitative and quantitative changes of leukocytes, erythrocytes and thrombocytes. Our work focusses on elucidating the causative membrane receptors (e.g. integrins), the signalling pathways, the involved cytokines and the role of the innate immune system in the form of granulocytes/monocytes. Our research also aims to identify new molecular targets for improved therapies.

We work on the following projects to uncover the pathologic functions of mutated JAK2 kinase (JAK2-V617F) as well as mutated calreticulin:

• Differential blockade of TNF receptors 1 and 2 as well as interleukin-6 in a JAK2-V617F mouse model
• Molecular mechanisms of induction of inflammatory cytokines during integrin activation in JAK2-V617F-positive granulocytes
• Activation of β1 and β2 integrins on leukocytes: role of JAK2-V617F and mutated calreticulin during thrombus formation

Methodically, we use the following experimental models:

• cell lines (myeloic and lymphatic progenitor cell lines), expressing the mutated JAK2 kinase and mutated calreticulin
• various mouse models with PV- or ET-like disease phenotypes
• human hematopoietic cells from patients with JAK2 and calreticulin mutations

Our research comprises a broad spectrum of in vitro and in vivo techniques. Together with our cooperation partners, we use state of the art biochemical and molecular biology approaches, proteomics, in vivo models of thrombosis and intravital 2-photon microscopy.

Contact

Prof. Dr. med. Thomas Fischer