Molecular pathophysiology of Myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders characterized by the excessive proliferation of one or more myeloid lineages, often driven by mutations activating the JAK-STAT signaling pathway. Despite substantial advances in understanding the molecular landscape of these disorders, many aspects of their initiation, progression, and phenotypic diversity remain unresolved. This doctoral thesis focuses on elucidating the molecular mechanisms underlying MPN pathophysiology, with particular emphasis on the interplay between genetic predisposition and dysregulated cytokine signaling. The work integrates experimental modeling and molecular analysis to explore how germline JAK2 variants and modulation of JAK-STAT signaling through erythropoietin receptor (EPOR) contribute to hematopoietic regulation and disease evolution. To address the role of JAK2 germline variants in MPN pathogenesis, we generated and characterized unique mouse model bearing germline Jak2-R1063H mutation, previously identified in MPN patients in cooperation with oncogenic JAK2-V617F mutation and associated with increased risk of leukemic transformation. The Jak2-R1063H mice exhibited increased mortality, enhanced thrombopoiesis independently of thrombopoietin levels with production of hyperreactive platelets...