Waldenström macroglobulinemia is a rare blood cell cancer characterized by an excess of abnormal white blood cells in the bone marrow. These abnormal cells have characteristics of both white blood cells (lymphocytes) called B cells and more mature cells derived from B cells known as plasma cells. These abnormal cells with both lymphocyte and plasma characteristics are known as lymphoplasmacytic cells. Due to these cells, Waldenström macroglobulinemia is classified as a lymphoplasmacytic lymphoma. In Waldenström macroglobulinemia, these abnormal cells produce excess amounts of IgM, the largest of a type of protein known as an immunoglobulin; the overproduction of this large protein contributes to the condition's name (macroglobulinemia).

Waldenström macroglobulinemia usually begins in a person's sixties and is a slow-growing (indolent) cancer. Some affected individuals have elevated levels of IgM and lymphoplasmacytic cells but no symptoms of the condition; in these cases, the disease is usually found incidentally by a blood test taken for another reason. These individuals are diagnosed with smoldering (or asymptomatic) Waldenström macroglobulinemia. It can be many years before a person with the condition develops noticable signs and symptoms.

The most common signs and symptoms to first appear in people with Waldenström macroglobulinemia are weakness and extreme tiredness (fatigue) caused by a shortage of red blood cells (anemia). Affected individuals can also experience general symptoms such as fever, night sweats, and weight loss. Some people with Waldenström macroglobulinemia develop a loss of sensation and weakness in the limbs (peripheral neuropathy). Doctors are unsure why this feature occurs, although they speculate that the IgM protein attaches to the protective covering of nerve cells (myelin) and breaks it down. The damaged nerves cannot carry signals normally, leading to neuropathy.

Other features of Waldenström macroglobulinemia are due to the accumulation of lymphoplasmacytic cells in different tissues. For example, accumulation of these cells can lead to an enlarged liver (hepatomegaly), spleen (splenomegaly), or lymph nodes (lymphadenopathy). In the bone marrow, the lymphoplasmacytic cells interfere with normal blood cell development, causing a shortage of healthy blood cells (pancytopenia).

Several other signs and symptoms of Waldenström macroglobulinemia are related to the excess amounts of IgM. Increased IgM can thicken blood and impair circulation, causing a condition known as hyperviscosity syndrome. Features related to hyperviscosity syndrome include bleeding in the nose or mouth, blurring or loss of vision, headache, dizziness, and confusion. In some affected individuals, IgM and other immunoglobulins react to cold temperatures to form gel-like clumps that block blood flow in areas exposed to the cold, such as the hands and feet. These clumped proteins are referred to as cryoglobulins, and their clumping causes a condition known as cryoglobulinemia. Cryoglobulinemia can lead to pain in the hands and feet or episodes of Raynaud phenomenon, in which the fingers and toes turn white or blue in response to cold temperatures. The IgM protein, along with another protein called amyloid, can build up in organs and interfere with their normal function. This buildup causes a condition called amyloidosis. Organs that are typically affected by amyloidosis include the heart, kidneys, liver or spleen. Affected individuals can experience weakness, fatigue, shortness of breath, irregular heartbeat, or joint pain.

It is not clear what causes Waldenström macroglobulinemia, though it is likely to result from a combination of genetic changes. The most common known genetic change associated with this condition is a variant (also called mutation) in the MYD88 gene, which is found in more than 90 percent of affected individuals. Another gene commonly associated with Waldenström macroglobulinemia, CXCR4, is altered in approximately 30 percent of affected individuals (most of whom also have the MYD88 gene variant).

The proteins produced from the MYD88 and CXCR4 genes are both involved in signaling within cells. The MyD88 protein relays signals that help prevent the self-destruction (apoptosis) of cells, thus aiding in cell survival. The CXCR4 protein stimulates signaling pathways inside the cell that help regulate cell growth and division (proliferation) and cell survival. Variants in these genes lead to production of proteins that are constantly turned on (overactive). Excessive signaling through these overactive proteins allows survival and proliferation of abnormal cells that should undergo apoptosis, which likely contributes to the accumulation of lymphoplasmacytic cells in Waldenström macroglobulinemia.

Other genetic changes believed to be involved in Waldenström macroglobulinemia have not yet been identified. Studies have found that certain regions of DNA are deleted or added in some people with the condition; however, researchers are unsure which genes in these regions are important for development of the condition. The variants that cause Waldenström macroglobulinemia are acquired during a person's lifetime and are present only in the abnormal blood cells.

Normal Function

The CXCR4 gene provides instructions for making a receptor protein that spans the outer membrane of cells, specifically white blood cells and cells in the brain and spinal cord (central nervous system). Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. After attachment of its ligand, called SDF-1, the CXCR4 protein turns on (activates) signaling pathways inside the cell. These pathways help regulate cell growth and division (proliferation), the process by which cells mature to carry out specific functions (differentiation), and cell survival. Once signaling is stimulated, the CXCR4 protein is removed from the cell membrane (internalized) and broken down so it can no longer activate the signaling pathways.

The CXCR4 receptor is also involved in the movement (migration) of cells. Cells that have the CXCR4 protein in their membrane are attracted to SDF-1. High levels of this ligand are found in the bone marrow, which helps certain blood cells migrate to and stay in the bone marrow until they are needed elsewhere in the body. Retention of early blood cells known as hematopoietic stem cells in the bone marrow is important to ensure that stem cells are available when needed. White blood cells also remain in the bone marrow until they are needed in the body to fight infection.

Health Conditions Related to Genetic Changes

Waldenström macroglobulinemia

Mutations in the CXCR4 gene are found in approximately 30 percent of people with Waldenström macroglobulinemia. This rare form of blood cancer is characterized by an excess of abnormal white blood cells called lymphoplasmacytic cells in the bone marrow and overproduction of a protein called IgM. These mutations are acquired during a person's lifetime and are present only in the abnormal white blood cells. This type of genetic change, called a somatic mutation, is not inherited. Waldenström macroglobulinemia is thought to result from multiple genetic changes, one of which can be a CXCR4 gene mutation.

CXCR4 gene mutations involved in Waldenström macroglobulinemia lead to production of an abnormally short CXCR4 protein that cannot be internalized, prolonging signaling activated by the protein. This signaling leads to enhanced survival and proliferation of cells containing the abnormal protein, which may contribute to the abundance of lymphoplasmacytic cells characteristic of Waldenström macroglobulinemia.

Other disorders

At least nine mutations in the CXCR4 gene have been found to cause WHIM syndrome, a condition characterized by impaired immune function and recurrent bacterial and viral infections. Several of the mutations that cause WHIM syndrome are also found in individuals with Waldenström macroglobulinemia (described above). However, in WHIM syndrome, the mutations are typically inherited and are found in every cell of the body (known as germline mutations).

As in Waldenström macroglobulinemia, the CXCR4 gene mutations that cause WHIM syndrome impair internalization of the CXCR4 protein. Researchers suggest that white blood cells that have the CXCR4 protein in their membrane longer than usual are abnormally retained in the bone marrow (a condition known as myelokathexis). A lack of these immune cells circulating through the body likely impairs the body's immune reaction to bacteria and viruses, leading to the recurrent infections common in WHIM syndrome.

Other Names for This Gene

• C-X-C chemokine receptor type 4
• CD184
• CD184 antigen
• chemokine (C-X-C motif) receptor 4
• CXCR4_HUMAN
• D2S201E
• FB22
• fusin
• HM89
• HSY3RR
• LAP-3
• LAP3
• LCR1
• LESTR
• leukocyte-derived seven transmembrane domain receptor
• lipopolysaccharide-associated protein 3
• LPS-associated protein 3
• neuropeptide Y receptor Y3
• NPY3R
• NPYR
• NPYRL
• NPYY3R
• SDF-1 receptor
• seven transmembrane helix receptor
• seven-transmembrane-segment receptor, spleen
• stromal cell-derived factor 1 receptor

Genomic Location

Normal Function

The MYD88 gene provides instructions for making a protein involved in signaling within immune cells. The MyD88 protein acts as an adapter, connecting proteins that receive signals from outside the cell to the proteins that relay signals inside the cell. In particular, MyD88 transfers signals from certain proteins called Toll-like receptors and interleukin-1 (IL-1) receptors, which are important for an early immune response to foreign invaders such as bacteria. In response to signals from these receptors, the MyD88 adapter protein stimulates signaling molecules that turn on a group of interacting proteins known as nuclear factor-kappa-B. Nuclear factor-kappa-B regulates the activity of multiple genes, including genes that control the body's immune responses and inflammatory reactions. It also protects cells from certain signals that would otherwise cause them to self-destruct (undergo apoptosis).

Health Conditions Related to Genetic Changes

MyD88 deficiency

At least four mutations in the MYD88 gene have been found to cause a condition called MyD88 deficiency. Individuals with this condition develop recurrent bacterial infections. Unlike in Waldenström macroglobulinemia and other blood disorders (described below), the gene mutations that cause MYD88 deficiency are inherited and are found in every cell of the body (known as germline mutations). These mutations result in the production of a nonfunctional protein or no protein at all. As a result, the protein cannot relay signals that stimulate an immune response, which allows multiple severe infections to develop.

Waldenström macroglobulinemia

A particular mutation in the MYD88 gene is found in more than 90 percent of people with Waldenström macroglobulinemia. This rare form of blood cancer is characterized by an excess of abnormal white blood cells called lymphoplasmacytic cells in the bone marrow and overproduction of a protein called IgM. The mutation involved in this condition changes a single protein building block (amino acid) in the MyD88 protein, replacing the amino acid leucine with the amino acid proline at position 265 (written as Leu265Pro or L265P). The mutation is acquired during a person's lifetime and is present only in the abnormal white blood cells. This type of genetic change, called a somatic mutation, is not inherited. Waldenström macroglobulinemia is thought to result from multiple genetic changes, including the MYD88 gene mutation.

The altered MyD88 protein is constantly functioning (overactive). It stimulates the signaling molecules that activate nuclear factor-kappa-B, even without signals from outside the cell. Researchers suggest that abnormally active nuclear factor-kappa-B allows survival of abnormal cells that should undergo apoptosis, which may contribute to the accumulation of lymphoplasmacytic cells in Waldenström macroglobulinemia.

Other disorders

The L265P mutation is also found in about 50 to 80 percent of cases of a blood disorder called IgM monoclonal gammopathy of undetermined significance (IgM-MGUS). Individuals with this condition have slightly elevated levels of IgM in the blood. IgM-MGUS can transform into Waldenström macroglobulinemia (described above) or other blood cell cancers or disorders; when the MYD88 gene mutation is present in IgM-MGUS, the condition is more likely to progress.

Other cancers

The somatic L265P mutation in the MYD88 gene is also found in some cases of other blood cell cancers, including diffuse large B-cell lymphoma (DLBCL) and marginal zone lymphoma. The mechanism by which the mutation contributes to development of the condition is thought to be the same as in Waldenström macroglobulinemia (described above). The type of cancer that develops is likely determined by the type of cell that acquires the L265P mutation. This mutation is thought to be one of many genetic changes involved in the development of these cancers.

Other Names for This Gene

• MYD88_HUMAN
• MYD88D
• myeloid differentiation primary response 88
• myeloid differentiation primary response gene (88)
• myeloid differentiation primary response protein MyD88

Genomic Location

Waldenström macroglobulinemia is not inherited, and most affected people have no history of the disorder in their family. The condition usually arises from genetic changes in blood cells that are acquired during a person's lifetime (somatic variants), which are not inherited.

Some families seem to have a predisposition to the condition. Approximately 20 percent of people with Waldenström macroglobulinemia have a family member with the condition or another disorder involving abnormal B cells.

For individuals who do not have any symptoms, doctors may decide to "watch and wait" and not treat the disease right away. This can last many years for some individuals. For individuals requiring treatment, the type and severity of symptoms present, aggressiveness of the disease, and age all play a role in the type of therapy chosen.

Some affected individuals have a procedure called plasmapheresis, to reverse or prevent the symptoms associated with the thickening of the blood (hyperviscosity). This involves removing the blood, passing it through a machine that removes the part of the blood with the IgM antibody, and returning the blood to the body. This may be combined with other treatments such as various types of chemotherapy. Many different drugs can be used to manage this condition, both alone and/or in various combinations.

For many individuals, there is a delayed response to treatment and the best response sometimes occurs several months after the treatment ends. Although the condition is not curable, many individuals do have a long-term response to treatment. Those who relapse after treatment or do not respond to initial treatment may consider secondary therapies. There are also several new drugs and drug combinations that are being studied in clinical trials.

Waldenström macroglobulinemia affects an estimated 3 per million people each year in the United States. Approximately 1,000 to 1,500 new cases of the condition are diagnosed each year in this country, and white people are more likely to develop Waldenström macroglobulinemia than African Americans. For unknown reasons, the condition occurs twice as often in men than women.