Myelofibrosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2], Sujit Routray, M.D. [3]

Overview

Myelofibrosis, a myeloproliferative disorder, is characterized by the proliferation of megakaryocytes in the bone marrow, disrupted cytokine production, and reactive fibrosis resulting in bone marrow failure. The fibrosed and scarred bone marrow produces fewer and fewer normal functioning blood cells leading to pancytopenia and extramedullary hematopoiesis. It can mainly be associated with somatic mutation of the thrombopoietin receptor gene (MPL), the calreticulin (CALR) gene, or Janus kinase 2 (JAK2) gene but other genes can also be involved and it can also result in the setting of another primary insult.

Pathogenesis

• Polyclonal mesenchymal cells of the bone marrow such as, fibroblasts, osteoblasts, pericytes, endothelial cells, adipocytes, and reticular cells create a functional microenvironment, which maintains hematopoiesis. This maintenance takes place through cellular interactions via growth factors, adhesion molecules, cytokines, and extracellular matrix components along with the help of oxygen and calcium.
• Myelofibrosis is the result of pathologic interaction between hematopoietic progenitor and stromal cells leading to the activation and expansion of the stroma and the accumulation of reticulin and collagen fibers produced by mesenchymal cells.
• The development and progression of myelofibrosis involves the activation of Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway, which paves the way for the overproduction of abnormal megakaryocytes.
• The abnormally proliferated megakaryocytes produce cytokines such as platelet-derived growth factor (PDGF), transforming growth factor (TGF) beta, and basic fibroblast growth factor (bFGF) which are involved in the abnormal proliferation of fibroblasts, resulting in fibrosis.
• Myelofibrosis can result in the setting of somatic mutations in specific genes or it can also be secondary to other primary disorders.
• The somatic mutations driving the disorder can mainly involve the thrombopoietin receptor gene (MPL), the calreticulin (CALR) gene, or Janus kinase 2 (JAK2) gene.
• The fibrosis of bone marrow leads to extramedullary hematopoiesis involving the reticuloendothelial organs such as the liver and spleen. Rarely, the extramedullary hematopoiesis can also involve ectopic hematopoietic tissue which includes the skin, lymph nodes, pleura, gastrointestinal tract, peritoneum, central nervous system, and genital and urinary tracts.

Myelofibrosis is a clonal neoplastic disorder of hematopoiesis, the formation of blood cellular components. It is one of the myleoproliferative disorders, diseases of the bone marrow in which excess cells are produced. 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. In its early phase, myelofibrosis is characterized by elevated numbers of CD34-positive cells in the marrow, while the later phases involve marrow fibrosis with decreasing CD34 cells in the marrow and a corresponding increase in splenic and liver engorgement with CD34 cells. The result is extramedullary hematopoiesis, or blood cell formation occurring in sites other than the bone marrow, as the hemopoetic cells are forced to migrate to other areas, particularly the liver and spleen. This causes an enlargement of these organs. In the liver, the condition is called hepatomegaly. Enlargement of the spleen is called splenomegaly, which also contributes to causing pancytopenia, particurly 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.

Sites of Hematopoiesis

The principal site of extramedullary hematopoiesis in myelofibrosis is the spleen, which is usually markedly enlarged, sometimes weighing as much as 4000 g. As a result of massive splenomegaly, multiple subcapsular infarcts often occur in the spleen, meaning that oxygen supply to the spleen is interrupted, leading to partial or complete tissue death. Histologically, the spleen contains red blood cell precursors, granulocyte precursors, and megakaryocytes, with the megokarycytes prominent in their number and in their bizarre shapes. Megakaryocytes are believed to be involved in causing the secondary fibrosis seen in this condition. This bone marrow fibrosis is a result of inappropriate release of PDGF and TGF-ß from these neoplastic megakaryocytes. Sometimes, an unusual activity of the red blood cells, white blood cells, or platelets is also observed. The liver is often moderately enlarged, with foci of extramedullary hematopoiesis. Microscopically, lymph nodes also contain foci of hematopoiesis, but these are insufficient to cause enlargement. There are also reports of hematopoiesis taking place in the lungs. These cases are associated with hypertension in the pulmonary arteries. The bone marrow in a typical case is hypercellular and diffusely fibrotic. Both early and late in disease, megakaryocytes are often prominent and are usually dysplastic.

Genetics

• Development of myelofibrosis is the result of multiple genetic mutations.
• Genes involved in the pathogenesis of myelofibrosis include:

• JAK2
• CALR
• MPL

• Approximately 90% of those with myelofibrosis have one of these mutations. These mutations are not specific to myelofibrosis, and are linked to other myeloproliferative disorders, specifically 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.

References

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