Waldenström macroglobulinemia – MYD88 and CXCR4 genes.

Waldenström macroglobulinemia is a rare blood cell neoplasm characterized by an excess of lymphoplasmacytic cells in the bone marrow. This disease is classified as lymphoplasmacytic lymphoma. The abnormal cells have characteristics of B-cell lymphocytes and plasma cells. These abnormal cells produce excessive amounts of IgM.

This disease usually begins around age 60 and is a slow-growing neoplasm. Some affected individuals have elevated levels of IgM and lymphoplasmacytic cells but the disease may be asymptomatic until over the years it progresses to the symptomatic form. Affected people 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 decrease circulation, generating a hyperviscosity syndrome. Features related to hyperviscosity syndrome include nose and mouth bleeds, blurred vision or loss of vision, headache, dizziness, and ataxia. In some affected individuals, IgM proteins accumulate in the hands and feet, causing cryoglobulinemia. 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. Additionally, IgM protein can also accumulate in organs such as 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 attaches to and breaks down myelin.

Other features of Waldenström macroglobulinemia are due to the accumulation of lymphoplasmacytic cells in different tissues. For example, the accumulation of these cells can cause hepatomegaly, splenomegaly, or lymphadenopathy. In the bone marrow, lymphoplasmacytic cells interfere with normal blood cell development, causing pancytopenia. Furthermore, fatigue due to anemia is common in affected individuals. People with Waldenström macroglobulinemia are at increased risk of developing other types of cancer in the blood or in other tissues.

Waldenström macroglobulinemia is believed to be due to a combination of genetic changes. The most common known genetic change is a mutation in the MYD88 gene, which is found in more than 90% of affected individuals. Another gene associated with Waldenström macroglobulinemia is the CXCR4 gene, which is mutated in approximately 30% of affected people. Other genetic changes believed to be involved in Waldenström macroglobulinemia have not yet been identified.

The MYD88 gene, located on the short arm of chromosome 3 (3p22), encodes a protein involved in signaling within immune cells. The protein acts as a MyD88 adapter, connecting proteins that receive signals from outside the cell to proteins that transmit signals inside the cell. In particular, MyD88 transfers signals from Toll-like receptors and interleukin-1 (IL-1) receptors, which are important for a rapid immune response to foreign invaders such as bacteria. In response to signals from these receptors, the adapter protein MyD88 stimulates signaling molecules that are converted to 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 disease-associated mutation in the MYD88 gene replaces the amino acid leucine with the amino acid proline at position 265 (Leu265Pro or L265P). The altered MyD88 protein is constantly active, stimulating the signaling molecules that activate nuclear factor-kappa-B, even without signals from outside the cell. Abnormally active nuclear factor-kappa-B likely allows the survival of abnormal cells that must undergo apoptosis, which may contribute to the accumulation of lymphoplasmacytic cells in Waldenström macroglobulinemia.

The CXCR4 gene, located on the long arm of chromosome 2 (2q21), encodes a receptor protein that spans the outer membrane of cells, white blood cells, and specifically cells in the central nervous system. After binding of its ligand, SDF-1, the CXCR4 protein activates signaling pathways within the cell. These pathways help regulate cell growth, proliferation, differentiation, and survival. Once signaling is stimulated, the CXCR4 protein is shed from the cell membrane and broken down, which can no longer activate signaling pathways. The CXCR4 receptor is also involved in cell migration. Cells that have the CXCR4 protein on their membrane are attracted to SDF-1. High levels of this ligand are found in the bone marrow, which helps certain blood cells to migrate and stay in the bone marrow until they are needed in other parts of the body. The retention of hematopoietic stem cells in the bone marrow is important to ensure that they are available when needed. White blood cells also remain in the bone marrow until they are needed to fight infection. Mutations in the CXCR4 gene associated with Waldenström macroglobulinemia lead to the encoding of an abnormally short CXCR4 protein that cannot be internalized, prolonging protein-activated signaling. This signaling leads to increased survival and proliferation of cells containing the abnormal protein, which can contribute to the excess lymphoplasmacytic cells characteristic of Waldenström macroglobulinemia.

In general, Waldenström macroglobulinemia is not inherited, and most affected people have no family history of the disease, so this disease is due to somatic mutations. Some families seem to have a predisposition to the disease. About 20% of people with Waldenström´s macroglobulinemia have a family member with the disease or another disorder that involves abnormal B cells.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Waldenström Macroglobulinemia, by means of the complete PCR amplification of the exons of the MYD88 and CXCR4 genes, respectively, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).