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STAT5B as a novel prognostic marker of thrombosis risk in myeloproliferative neoplasms

Abstract
Myeloproliferative neoplasms (MPNs) are heterogeneous diseases arising from mutations in hematopoietic stem cells, resulting in the expansion of mature myeloid cells. Megakaryocyte (MK) dysplasia is a hallmark feature, where MKs drive various MPN pathologies. MPN disease driver mutations, including the most prevalent JAK2V617F, activate the JAK2-STAT5 pathway. STAT5 signaling has a key role in MPN. The main cause of death in MPN patients is thromboembolic events, and both MKs and JAK2V617F burden are linked to thrombosis development. However, identifying patients at high risk of thromboembolism remains a significant clinical challenge due to a lack of markers that can stratify the high level of heterogeneity in MPN disease. There are also sex-specific differences in MPN; men have more aggressive disease progression whereas women have more mature MK phenotypes and higher rates of venous thrombosis. The mechanisms of these sex-based differences are unknown. Our preliminary data reveal that increased STAT5B expression in MPN patients is associated with incidence of thromboembolic events. Increased STAT5B expression in a mouse MPN model results in more severe disease and increased MK differentiation. We also observe striking sex-specific differences in our data, reminiscent of human disease.We hypothesize that higher STAT5B levels in a JAK2V617F setting cause altered transcription, increased MK and platelet dysplasia and enhanced incidence of thrombosis, and that these effects of STAT5B are sex-specific as a result of regulation of estrogen receptor signaling. We will employ a novel MPN mouse model to determine the role of increased STAT5B expression on MK dysplasia, platelet function and thrombosis. We will perform transcriptomics on primary murine cells, and generate MPN cell line models using enhanced expression and CRISPR/Cas9 knockout systems to examine STAT5B-driven signaling and MK lineage regulation. These tools will enable us to assess the crosstalk between STAT5B, MK differentiation and estrogen receptor signaling to decipher sex-specific MPN phenotypes.Our project will represent the first attempt to account for sex-specific differences in MPN pathogenesis, potentially revealing a novel role for STAT5B as a sex-specific transcriptional regulator of hematopoiesis/megakaryopoiesis. We also expect to reveal the potential of increased STAT5B levels as a prognostic marker for risk of thromboembolic events and disease outcome in MPN. The study could have potential broad relevance for thrombotic disease and mechanisms behind sex-specific differences in other forms of blood neoplasia.The project will be led by Dr Heidi Neubauer, University Assistant at the University of Veterinary Medicine, Vienna. Dr Neubauer has a strong focus on signal transduction and hematological malignancies.
Lemma
STAT5B as a prognostic marker of thrombosis in MPN
Project leader
Neubauer Heidi
Duration
01.06.22-31.05.26
Programme
FWF Einzelprojekte
Type of Research
Basic research
Vetmed Research Units
Institute of Animal Breeding and Genetics, Unit for Functional Cancer Genomics
Funded by
FWF - Fonds zur Förderung der wissenschaftlichen Forschung, Wien, Austria

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