JAK2 mutations in polycythemia vera: from molecular origins to inflammatory pathways and clinical implications

Summary Polycythemia vera (PV) is a myeloproliferative neoplasm primarily driven by mutations in the JAK2 gene, most notably the V617F mutation, which occurs in nearly 97% of cases. This gain-of-function mutation overactivates the JAK-STAT pathway, a critical factor in developing the PV phenotype by stimulating excessive proliferation of the erythroblastic lineage. Diagnostic methods for PV focus on detecting the JAK2 mutation—primarily through polymerase chain reaction (PCR) and next-generation sequencing, which are essential for distinguishing PV from other disorders. The variant allele frequency (VAF) of JAK2 V617F also serves as an important prognostic marker, with higher VAF linked to both increased thrombotic risk and disease progression to myelofibrosis or acute leukemia. Thus, managing allele burden is central to treatment strategies. Given the genetic complexity of PV, personalized treatment approaches are essential. Current therapies focus on JAK2 signaling, with ropeginterferon alfa-2b and JAK inhibitors as primary or secondary treatments to reduce clonal expansion and control inflammation, and aspirin to prevent thrombotic events. Emerging treatments are exploring anti-inflammatory strategies, such as anti-IL-1β antibodies, and agents targeting iron metabolism to maintain hematocrit levels without phlebotomy, potentially improving quality of life. Overall, reducing JAK2 V617F burden and controlling inflammation are crucial for managing PV progression and improving patient outcomes, with ongoing research refining these therapeutic avenues to enhance long-term strategies.