These mutations are not specific to myelofibrosis, and are linked to other myeloproliferative neoplasms, specifically polycythemia vera and essential thrombocythemia.The V617F mutation to the JAK2 protein is found in approximately half of individuals with primary myelofibrosis. The V617F mutation is a change of valine to phenylalanine at the 617 position. Janus kinases (JAKs) are non-receptor tyrosine kinases essential for the activation of signaling that is mediated by cytokine receptors lacking catalytic activity. These include receptors for erythropoietin, thrombopoietin, most interleukins and interferon. JAK2 mutations are significant because JAK2 plays a role in controlling production of blood cells from hematopoietic stem cells. The V617F mutation appears to make hematopoietic cells more sensitive to growth factors that need JAK2 for signal transduction, which include erythropoietin and thrombopoietin.The MPL gene codes for a protein that acts as a receptor for thrombopoietin. A mutation in that gene, known as a W515 mutation, leads to the production of an abnormal thrombopoietin receptor protein, which results in the overproduction of abnormal megakaryocytes. The abnormal megakaryocytes stimulate other cells, the fibroblasts, to produce collagen in the bone marrow, by secreting PDGF and TGF-β1. Mechanism
Myelofibrosis is a clonal neoplastic disorder of hematopoiesis, the formation of blood cellular components. It is one of the myeloproliferative disorders, diseases of the bone marrow in which excess cells are produced at some stage. Production of cytokines such as fibroblast growth factor by the abnormal hematopoietic cell clone (particularly by megakaryocytes) leads to replacement of the hematopoietic tissue of the bone marrow by connective tissue via collagen fibrosis.
Primary myelofibrosis can begin with a blood picture similar to that found in polycythemia vera or chronic myeloid leukemia. Most people with myelofibrosis have moderate to severe anemia. Eventually thrombocytopenia, a decrease of blood platelets develops. When viewed through a microscope, a blood smear will appear markedly abnormal, with presentation of pancytopenia, which is a reduction in the number of all blood cell types: red blood cells, white blood cells, and platelets. Red blood cells may show abnormalities including bizarre shapes, such as teardrop-shaped cells, and nucleated red blood cell precursors may appear in the blood smear (leukoerythroblastic reaction). Normally, mature red blood cells in adults do not have a cell nucleus, and the presence of nucleated red blood cells suggests that immature cells are being released into the bloodstream in response to a very high demand for the bone marrow to produce new red blood cells. Immature white cells and platelets (large megakaryocytes) are also seen in blood samples, and basophil counts are increased. When late in the disease progression an attempt is made to take a sample of bone marrow by aspiration, it may result in a dry tap, meaning that where the needle can normally suck out a sample of semi-liquid bone marrow, it produces no sample because the marrow has been replaced with collagen fibers. A bone marrow biopsy will reveal collagen fibrosis, replacing the marrow that would normally occupy the space. Treatment
The one known curative treatment is allogeneic stem cell transplantation, but this approach involves significant risks.