Waldenstrom 's , macroglobulinemia ... (Waldenstrom macroglobulinemia) - Genes MYD88 and CXCR4.
Waldenström macroglobulinemia is a rare blood cell neoplasm characterized by excess lymphoplasmacytic cells in the bone marrow. This disease is classified as a lymphoplasmacytic lymphoma. Abnormal cells have characteristic B lymphocyte cells and plasma cells. These abnormal cells produce excessive amounts of IgM.
This disease usually begins around age 60 and is a slow growing malignancy. Some affected individuals have elevated levels of IgM and lymphoplasmacytic cells but the disease can be asymptomatic until over the years progresses to symptomatic form. Those affected may have fever, night sweats and weight loss. Other signs and symptoms of the disease are related to excess IgM, which can thicken the blood and reduce the circulation generating a hyperviscosity syndrome. Related characteristics hyperviscosity syndrome include nasal and mouth bleeding, blurred vision or loss of vision, headache, dizziness and ataxia. In some affected individuals, IgM proteins accumulate in the hands and feet, causing crioglobulinemia. Cryoglobulinemia can cause pain in the hands and feet or episodes of Raynaud's phenomenon, in which the fingers and toes turn white or blue in response to cold temperatures. In addition, the IgM protein can also accumulate in organs like the heart and kidneys, causing amyloidosis, which can lead to heart and kidney problems. Some people with Waldenström macroglobulinemia develop peripheral neuropathy, probably because the IgM protein binds to myelin and decomposes.
Other features of the macroglobulinemia are due to the accumulation of lymphocytes and plasma cells in different tissues. For example, the accumulation of these cells may cause hepatomegaly, splenomegaly and lymphadenopathy. In the bone marrow, lymphoplasmacytic cells interfere with the normal development of blood cells, causing pancytopenia. In addition, fatigue due to anemia is common in affected individuals. People with Waldenstrom macroglobulinemia have a higher risk of developing other types of blood cancer or other tissues.
It is believed that Waldenström macroglobulinemia is due to a combination of genetic changes. The most common known genetic change is a mutation in the gene MYD88, it found in over 90% of affected individuals. Another gene associated with Waldenstrom 's macroglobulinemia, is the CXCR4 gene which is mutated in approximately 30% of those affected. They have not yet been identified other genetic changes that are believed to be involved in Waldenstrom 's macroglobulinemia.
MYD88 gene, located on the short arm of chromosome 3 (3p22), encodes a protein involved in signaling within the immune cells. The protein acts as a MyD88 adapter protein connection receiving signals from outside the cell to proteins that transmit signals within the cell. In particular, signals transferred MyD88 Toll - like receptors and interleukin-1 (IL-1), which are important for rapid immune response to foreign invaders such as bacteria. In response to signals from these receptors, it stimulates MyD88 adapter protein signaling molecules that become the nuclear factor kappa-B. The nuclear factor kappa-B regulates the activity of multiple genes, including genes that control the body 's immune response and inflammatory reactions. It also protects cells from certain signals that would otherwise lead to apoptosis. A mutation in the gene associated with the disease MYD88, replaces the amino acid leucine by the amino acid proline at position 265 (Leu265Pro or L265P). The MyD88 protein is altered constantly active, stimulating signaling molecules that activate nuclear factor-kappa-B, even without signals from outside the cell. Is likely to abnormally active nuclear factor-kappa-B to survival of abnormal cells should undergo apoptosis, which may contribute to the accumulation of lymphocytes and plasma cells in Waldenström macroglobulinemia.
CXCR4 gene, located on the long arm of chromosome 2 (2q21), encoding a receptor protein that extends across the outer membrane of the cells, white blood cells and specifically the cells in the central nervous system. After binding of its ligand, SDF-1, CXCR4 protein activates signaling pathways within the cell. These pathways help regulate the growth, proliferation, differentiation and cell survival. Once the signaling is stimulated, the CXCR4 protein is removed from the cell membrane and decomposes, it can not activate signaling pathways. CXCR4 receptor is also involved in cell migration. Cells having CXCR4 protein on their membrane are attracted to SDF-1. High levels of this ligand found in the bone marrow, which helps certain blood to migrate and remain in the bone marrow until needed elsewhere in the body cells. Retention hematopoietic stem cells in the bone marrow is important to ensure they are available when needed. White blood cells also remain in the bone marrow until needed to fight infection. CXCR4 gene mutations associated with Waldenström macroglobulinemia lead to an abnormally short encoding CXCR4 protein that can not be internalized, prolonging activated signaling protein. This signaling leads to enhanced survival and proliferation of the cells containing the abnormal protein, which may contribute to excess characteristic lymphoplasmacytic cells macroglobulinemia.
Overall, Waldenstrom 's macroglobulinemia is not inherited, and most of those affected have no history of the disease in your family, so this disease is caused by somatic mutations. Some families seem to have a predisposition to the disease. Approximately 20% of people with Waldenstrom macroglobulinemia have a relative with the disease or other disorder involving abnormal B cells.
Tests performed in IVAMI: in IVAMI perform detection of mutations associated with Waldenström macroglobulinemia, by complete PCR amplification of the exons of the genes MYD88 and CXCR4, 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).