Myelofibrosis

Myelofibrosis is a clonal myeloproliferative neoplasm driven by activating mutations in the JAK-STAT pathway. Common driver mutations include JAK2V617F, CALR, and MPL. The abnormal clone particularly disrupts megakaryocyte development and signalling. These megakaryocytes release cytokines that stimulate reticulin and collagen deposition by marrow fibroblasts. Fibrosis progressively replaces the normal marrow environment. Red-cell, white-cell, and platelet production then become ineffective or unstable, producing anemia and variable leukocyte or platelet counts. The spleen and liver attempt to compensate by making blood cells outside the marrow, a process called extramedullary hematopoiesis. This is why splenomegaly is not simply an incidental enlargement: it reflects both disease burden and a shift in where hematopoiesis is occurring. The mutation pattern helps classify risk but does not replace clinical assessment. When JAK2, CALR, and MPL are all absent, the disease is described as triple-negative and is associated with higher-risk biology.