Myelofibrosis

Primary myelofibrosis is a relatively rare bone marrow/blood cancer. It is currently classified as a myeloproliferative neoplasm, in which the proliferation of an abnormal clone of hematopoietic stem cells in the bone marrow and other sites results in fibrosis, or the replacement of the marrow with scar tissue. Primary myelofibrosis is a relatively rare bone marrow/blood cancer. It is currently classified as a myeloproliferative neoplasm, in which the proliferation of an abnormal clone of hematopoietic stem cells in the bone marrow and other sites results in fibrosis, or the replacement of the marrow with scar tissue. The term myelofibrosis alone usually refers to primary myelofibrosis (PMF), also known as chronic idiopathic myelofibrosis (cIMF); the terms idiopathic and primary mean that in these cases the disease is of unknown or spontaneous origin. This is in contrast with myelofibrosis that develops secondary to polycythemia vera or essential thrombocythaemia. Myelofibrosis is a form of myeloid metaplasia, which refers to a change in cell type in the blood-forming tissue of the bone marrow, and often the two terms are used synonymously. The terms agnogenic myeloid metaplasia and myelofibrosis with myeloid metaplasia (MMM) were also used to refer to primary myelofibrosis. The primary feature of primary myelofibrosis is bone marrow fibrosis, but it is often accompanied by: There is an association between mutations to the JAK2, CALR, or MPL gene and myelofibrosis. Approximately 90% of those with myelofibrosis have one of these mutations and 10% carry none of these mutations. 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. 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. The decrease in hematopoietic tissue impairs the patient's ability to generate new blood cells, resulting in progressive pancytopenia, a shortage of all blood cell types. However, the proliferation of fibroblasts and deposition of collagen is a secondary phenomenon, and the fibroblasts themselves are not part of the abnormal cell clone. In primary myelofibrosis, progressive scarring, or fibrosis, of the bone marrow occurs, for the reasons outlined above. The result is extramedullary hematopoiesis, i.e. blood cell formation occurring in sites other than the bone marrow, as the haemopoetic cells are forced to migrate to other areas, particularly the liver and spleen. This causes an enlargement of these organs. In the liver, the abnormal size is called hepatomegaly. Enlargement of the spleen is called splenomegaly, which also contributes to causing pancytopenia, particularly thrombocytopenia and anemia. Another complication of extramedullary hematopoiesis is poikilocytosis, or the presence of abnormally shaped red blood cells. Myelofibrosis can be a late complication of other myeloproliferative disorders, such as polycythemia vera, and less commonly, essential thrombocythaemia. In these cases, myelofibrosis occurs as a result of somatic evolution of the abnormal hematopoietic stem cell clone that caused the original disorder. In some cases, the development of myelofibrosis following these disorders may be accelerated by the oral chemotherapy drug hydroxyurea.