Work

Targeting PAR1 activation in JAK2V617F-driven philadelphia-negative myeloproliferative neoplasms: Unraveling its role in thrombosis and disease progression

Year: 2025

Type: article

Abstract: Philadelphia chromosome-negative myeloproliferative neoplasms (Ph - MPNs) are clonal disorders marked by high morbidity and mortality, driven by uncontrolled myeloid proliferation from hematopoietic stem/progenitor cells (HSCs) and associated with a significant risk of thrombosis. This study explored the relationship between JAK2 V617F and protease-activated receptor 1 (PAR1) by examining PAR1 expression and activation across various hematopoietic stem/progenitor cell (HSPC) subgroups, assessing their contribution to the hypercoagulable state in Ph - MPNs. We investigated the effects of thrombin, a PAR1 antagonist (vorapaxar), and a JAK2 inhibitor (ruxolitinib) on Ph - MPN cells. Mononuclear cells (MNCs) were isolated from Ph-MPN patients ( n = 18), cord blood (CB) samples ( n = 5) and healthy volunteers ( n = 11). Specific subpopulations were sorted and analyzed for PAR1 expression and JAK2 V617F status using qRT-PCR. PAR1 expression changes, along with other PAR pathway-related genes, were assessed post-treatment. Our results revealed that most PAR1 + cells (∼95 %) co-expressed CD34 + , with a smaller JAK2V617F + PAR1 + population lacking CD34. PAR1 expression was significantly higher in Ph-MPN MNCs compared to CB ( p = 0.0005), particularly in EMP, HSC/EPC, and EPC subsets. Thrombin treatment reduced surface PAR1 expression, while PAR1 antagonist treatment further decrease the expression level. Combined PAR1 antagonist and ruxolitinib treatment significantly downregulated PAR1 expression ( p < 0.0001), and several PAR-pathway-related genes were notably downregulated after treatment. This study highlights that elevated PAR1 expression in primitive hematopoietic subpopulations is linked to disease progression and thrombosis in Ph - MPNs, suggesting PAR1 as a potential therapeutic target. Combining PAR1 antagonists with JAK2 inhibitors shows promise in reducing PAR1 expression and mitigating thrombotic events in Ph - MPN patients. Key findings of our study include: ● Elevated PAR1 Expression: We identified significantly increased PAR1 expression in primitive hematopoietic subpopulations of Ph-MPN patients compared to controls. ● PAR1 Activation and Thrombosis: Our results suggest that PAR1 activation contributes to the hypercoagulable state observed in Ph-MPNs, offering a new avenue for therapeutic intervention. ● Therapeutic Implications: We demonstrated that the combination of PAR1 antagonists and JAK2 inhibitors effectively reduces PAR1 expression and downregulates thrombo-inflammatory pathways, indicating potential for improved clinical outcomes.

Source: Neoplasia

DOI: 10.1016/j.neo.2025.101153

Authors: İldeniz USLU-BIÇAK, Meliha NALÇACI, Selçuk SÖZER

Institution: Istanbul University

Language: English

Topic: Myeloproliferative Neoplasms: Diagnosis and Treatment

Subfield: Genetics

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,530