Waldenström macroglobulinemia (WM) is a rare type of cancer that affects a specific group of white blood cells called B lymphocytes, which are part of the immune system. These B cells normally mature into plasma cells that produce antibodies to fight infections. In WM, there is an abnormal, uncontrolled growth of a clone of B cells that have features of both lymphocytes and plasma cells. This leads to the excessive production of a particular type of antibody called IgM, which accumulates in the blood and causes many of the disease’s symptoms.
The root cause of Waldenström macroglobulinemia lies in genetic mutations that occur in these B cells during their development. One of the most significant and common mutations found in WM patients is in a gene called MYD88. This gene plays a crucial role in the immune system by helping cells respond to infections and inflammation. In WM, a specific mutation known as MYD88 L265P changes the way this gene functions, causing the B cells to grow and survive abnormally. This mutation is present in the majority of WM cases and is considered a key driver of the disease.
Alongside MYD88 mutations, changes in another gene called CXCR4 are also frequently observed in WM. CXCR4 normally helps regulate the movement and localization of B cells within the body. Mutations in CXCR4 can further promote the survival and proliferation of the malignant B cells, contributing to disease progression. These genetic alterations disrupt the normal balance of cell growth and death, allowing the cancerous cells to accumulate.
The process begins in the bone marrow, where B cells mature. Normally, B cells undergo a tightly controlled development process, including rearrangement of their DNA to produce diverse antibodies. However, in WM, errors during this process lead to the emergence of a clone of B cells with the MYD88 mutation and sometimes CXCR4 mutations. These mutated cells then expand uncontrollably, producing large amounts of IgM antibody. The excess IgM thickens the blood, causing symptoms like fatigue, vision problems, and bleeding.
Other factors may contribute to the development of WM, although they are less well understood. Age is a significant risk factor, as WM typically affects older adults. Family history also plays a role, suggesting that inherited genetic predispositions might increase susceptibility. Environmental exposures, such as to certain chemicals or radiation, have been proposed but lack definitive proof.
At the cellular level, the mutated B cells in WM show abnormal signaling pathways that promote their growth and prevent normal cell death. The MYD88 mutation activates a signaling cascade involving proteins like IRAK and NF-kB, which are responsible for cell survival and inflammation. This constant activation creates an environment where the malignant cells thrive. The CXCR4 mutations can enhance signals that help the cells avoid dying and stick to supportive niches in the bone marrow.
The excessive IgM produced by these cells is not just a marker of the disease but also causes many complications. High levels of IgM increase blood viscosity, leading to poor circulation and symptoms such as headaches, dizziness, and bleeding. The abnormal cells can also infiltrate organs like the lymph nodes, spleen, and liver, causing enlargement and dysfunction.
In summary, Waldenström macroglobulinemia is caused primarily by genetic mutations in B cells, especially the MYD88 L265P mutation, which disrupt normal immune cell function and lead to uncontrolled growth and antibody production. Additional mutations, such as those in CXCR4, further support the survival and expansion of these malignant cells. These genetic changes, combined with factors like age and possibly environmental influences, result in the development of this complex blood cancer.
