Idiopathic myelofibrosis (Primary myelofibrosis) - Genes JAK2, MPL, CALR and TET2.
Primary myelofibrosis is a disease characterized by fibrosis in the bone marrow. Because fibrosis, bone marrow can not produce enough normal blood cells. Blood cell deficiency causes many of the signs and symptoms of primary myelofibrosis.
Initially, most people with primary myelofibrosis no signs or symptoms. Eventually, the fibrosis may lead to a reduction in the number of red blood cells (erythrocytes), white cells (leukocytes) and platelets. Often, anemia causes fatigue or shortness of breath. A loss of leukocytes can lead to increased infections, and reduction of platelets may cause easy bleeding or bruising. Because hematopoiesis in bone marrow is interrupted, other organs such as liver or spleen can begin producing blood cells. This process, called extramedullary hematopoiesis, often leads to splenomegaly or hepatomegaly. People with splenomegaly may feel pain or bloating, especially below the ribs on the left side. Other common signs and symptoms of primary myelofibrosis include fever, night sweats and bone pain. This disease is most often diagnosed in people aged 50 to 80 years of age, but can be diagnosed at any age.
This process is due in most cases to mutations in JAK2, MPL, CALR and TET2 genes. Some people with primary myelofibrosis have a mutation in any of these genes.
The JAK2 gene, located on the short arm of chromosome 9 (9p24), encodes a protein that promotes the growth and cell proliferation. This protein is part of the signaling pathway JAK / STAT, which transmits chemical signals from outside the cell to the cell nucleus. The JAK2 protein is particularly important to control the production of blood cells from hematopoietic stem cells. Mutations of the JAK2 gene are associated with somatic primary myelofibrosis. The V617F mutation is found in about half of those affected. A small number of people have mutations in exon 12 of the gene. These mutations of the JAK2 gene give rise to a constitutively active protein JAK2, which leads to overproduction of abnormal megakaryocytes. These megakaryocytes stimulate other cells to collagen release, causing the formation of scar tissue. Because fibrosis, bone marrow can not produce enough normal blood cells, leading to the signs and symptoms of the disease.
The MPL gene, located on chromosome 1 cortodel arm (1p34), encoding the protein thrombopoietin receptor, which promotes cell growth and proliferation. This receptor is particularly important for the proliferation of megakaryocytes, involved in blood clotting. It is also likely that this protein plays a role in the maintenance of hematopoietic stem cells. The thrombopoietin receptor is activated when aggregates of thrombopoietin bind to it. The thrombopoietin receptor stimulates activated signaling pathway JAK / STAT, which transmits chemical signals from outside the cell to the cell nucleus and is important to control the production of blood cells. Several mutations have been identified in the MPL gene in some people with primary myelofibrosis. Primary myelofibrosis is associated with gene mutations known as MPL W515 mutations. These mutations result in a protein constitutively activated receptor thrombopoietin, which induces overproduction of abnormal megakaryocytes. These megakaryocytes stimulate other cells to collagen release, stimulating the formation of scar tissue. Because fibrosis, bone marrow can not produce enough normal blood cells, leading to the signs and symptoms of the disease.
The CALR gene, located on the short arm of chromosome (19p13.3-p13.2) encoding calreticulin protein. This protein is found in various parts of the cell, including inside the endoplasmic reticulum (ER), cytoplasm, and cell outer surface. ER is involved in the processing and transport proteins, and inside this structure, calreticulin ensures the proper folding of proteins newly formed. The ER is also a storage location for calcium ions, and calreticulin is involved in maintaining the correct concentrations of calcium ions in the structure. Through the regulation of calcium and other mechanisms, it is believed that calreticulin exercises control of gene activity and proliferation, migration, adhesion and cell apoptosis. The function of this protein is important for immune function and healing heridas.Las somatic mutations in exon 9 of the gene CALR associated with primary myelofibrosis, although the effect of the genetic changes in calreticulin function is unknown.
The TET2 gene, located on the long arm of chromosome 4 (4q24), encoding a protein whose function is unknown. Based on the function of similar proteins, it is believed that TET2 protein is involved in regulating the transcription process. Although this protein is found throughout the body, it can play a particularly important role in the production of blood cells from hematopoietic stem cells. The TET2 protein appears to act as a tumor suppressor. Somatic mutations in the gene are associated TET2 with primary myelofibrosis. However, it is unclear what role genetic mutations TET2 in the development of primary myelofibrosis.
In general, this condition is not inherited but arises from somatic gene mutations that occur in the first cells that form the blood after conception.
Tests in IVAMI: in IVAMI perform detection of mutations associated with primary myelofibrosis, by complete PCR amplification of the exons of JAK2, MPL, CALR and TET2 genes, respectively, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).