Funding tool: Basic research projects
Project-ID: LSC20-004
Project start: 01. Jänner 2022
Project end: will follow
Runtime: 36 months / ongoing
Funding amount: € 287.909,00

Brief summary:
Myeloproliferative neoplasms (MPNs) – polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) – are a group of haematologic diseases potentially evolving to acute myeloid leukaemia (AML). The pathogenesis of MPNs is dependent on activation of a specific signalling pathway, the Janus Kinase (JAK) –Signal Transducer and Activator of Transcription (STAT) pathway. The majority of MPNs is driven by mutation in one member of the JAK family, the JAK2V617F mutation. In ET and PMF more than 70% of the JAK2 non-mutated patients carry mutations in the calreticulin (CALR) gene. Both mutations lead to aberrant activation of the JAK-STAT cascade, which results in increased numbers of blood cells and enlarged spleen. Therefore, inhibition of JAK-STAT pathway is a relevant therapeutic strategy. Ruxolitinib, a JAK1/JAK2 inhibitor, has been approved for the treatment of intermediate and high risk PMF and MF as well as for PV resistant against hydroxyurea. Although Ruxolitinib treatment ameliorates the disease and increases the survival, it is not curative and patients require long-term treatment. In addition, it is associated with different side effects, such as recurrent infections due to its suppressive effects on the immune system. In particular, Ruxolitinib treatment leads to a severe impairment of natural killer (NK) cell survival and activity. NK cells are innate lymphocytes providing the first line of defence against virally infected and transformed cells. Our previous data suggest that the NK cell suppressive effects of Ruxolitinib are due to inhibition of JAK1 and not JAK2. We hypothesise that, in contrast to currently used JAK1/2 inhibitors, novel inhibitors specifically targeting JAK2 would ameliorate the mutant CALR-driven disease without suppressing the innate immune system. The study will pursue four objectives. First, using a mouse model of mutant CALR-driven MPN, we plan to investigate the effects of mutant CALR on NK cell development and function at different disease stages. Second, we will elucidate their sensitivity to JAK1/2 vs. JAK2-specific inhibition. Third, we aim to study the effects of JAK2-specific inhibitors on disease progression in a mouse model and compare the efficiency of the treatment as well as suppressive effects on NK cells with Ruxolitinib. Fourth, we will analyse primary human NK cells derived from mutated CALR+ ET or PMF patients (before Ruxolitinib treatment) and assess their functionality and vulnerability to JAK2-specific inhibitors. By assessing the efficacy and immune suppressive side effects of currently developed JAK2-specific inhibitors in mutated CALR-driven MPN, the study will provide data which might influence the rational for usage of JAK2-specific inhibitors in the clinics.