Do We Know What Causes Waldenstrom Macroglobulinemia?

Some risk factors can make a person more likely to get Waldenstrom macroglobulinemia (WM), but often it’s not clear exactly how these factors might increase risk.

Scientists have learned how certain changes in the DNA inside normal lymphocytes can make them become lymphoma or multiple myeloma cells. Changes in the DNA of some lymphoma cells can also cause them to make high levels of IgM, which leads to most of the symptoms of WM.

The DNA inside our cells makes up our genes – the instructions for how our cells function. We tend to look like our parents because they are the source of our DNA. But DNA affects more than how we look.

• Some genes control when cells grow, divide to make new cells, and die at the right time. They are called oncogenes.
• Other genes slow down cell division or make cells die at the right time. They are called tumor suppressor genes.

Cancers can be caused by DNA changes that turn on oncogenes or turn off tumor suppressor genes.

Some people inherit DNA changes from a parent that increase their risk for certain types of cancer. Researchers are studying families that have many cases of WM to try to find the genes that might cause this disorder in some people.

The DNA changes found in WM cells are usually acquired after birth (not passed on from a parent). Some of these acquired changes may have outside causes, but often they occur for no apparent reason. They seem to happen more often as we age, which might help explain why WM usually occurs in older people.

Recent research has found that about 9 times out of 10, WM cells have a mutation (change) in a gene known as MYD88, which normally helps immune system cells signal each other and helps keep them alive. The DNA change in this gene might make it stay turned on all the time, which might help the WM cells survive longer than they should.

Sometimes, WM cells have other kinds of DNA changes. In each human cell, the DNA is packaged in 23 pairs of chromosomes. In some WM cells, a piece of a chromosome is missing. This is called a deletion. The most common chromosome defect seen in WM is a deletion of part of chromosome 6. It’s not clear exactly which genes this might affect.

Another type of chromosome defect in WM is called a translocation. In a translocation, a piece of one chromosome becomes attached to a different chromosome. Chromosome changes like these can cause oncogenes to be turned on or tumor suppressor genes turned off.

Researchers have found that some patients with WM have important changes or defects in other bone marrow cells. These changes might also help cancer cells grow. Certain cells in the bone marrow called dendritic cells release a hormone called interleukin-6 (IL-6) that helps normal plasma cells and plasmacytoid lymphocytes grow. Excess IL-6 production by these cells appears to be an important factor in the development of WM.

Scientists are learning about the exact gene changes that cause WM. But even though they have found some of these gene changes, they still do not know why these changes occur.