Understanding Myelofibrosis and the Central Role of JAK Pathway Dysregulation

Myelofibrosis is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, abnormal blood cell production, and progressive splenomegaly. Its pathogenesis centers on clonal mutations—most commonly involving JAK2, CALR, or MPL—that drive hyperactive signaling in the JAK-STAT pathway. This dysregulation leads to uncontrolled proliferation of myeloid cells, inflammatory cytokine release, and the fibroblast activation that underpins marrow scarring. Over time, this disrupts normal hematopoiesis and contributes to hallmark symptoms such as anemia, constitutional complaints, and organomegaly. Targeting the JAK pathway directly addresses these mechanisms by reducing aberrant signaling, improving cytokine-mediated symptoms, and restoring more balanced hematopoietic activity. JAK inhibitors therefore play a foundational role in modifying disease biology and alleviating the substantial symptom burden associated with myelofibrosis.