What Causes Chronic Lymphocytic Leukemia (CLL)?

We know some of the risk factors for chronic lymphocytic leukemia (CLL), but the exact cause of CLL in most people is not known.

Even though we still don’t know what causes CLL in most people, researchers have made a lot of progress. They’ve begun to understand how certain changes in the DNA in certain bone marrow cells may cause CLL to develop.

Changes in genes and chromosomes can lead to cancer

Cancer (including CLL) is caused by changes in the DNA inside our cells. DNA is the chemical in our cells that makes up our genes, which control how our cells function. The DNA in each cell is in long strands called chromosomes.

Our DNA, which comes from both our parents, affects more than just how we look.

Different genes have different functions. Some genes normally help control when our cells grow, divide to make new cells, or repair mistakes in DNA. They also cause cells to die when they’re supposed to.

If these genes aren’t working properly, it can lead to cells growing out of control. For example:

• Oncogenes: Changes in genes that normally help cells grow, divide, or stay alive can lead to these genes being more active than they should be, causing them to become oncogenes. These genes can result in cells growing out of control.
• Tumor suppressor genes: Genes that normally help keep cell division under control or cause cells to die at the right time are known as tumor suppressor genes. Changes that turn off these genes can result in cells growing out of control.
• DNA repair genes: Some genes normally help detect and repair mistakes in a cell’s DNA. Changes that turn off these DNA repair genes can result in the buildup of DNA changes within a cell, which might lead to them growing out of control.

Any of these types of DNA changes might lead to cells growing out of control, which could lead to cancer. To learn more, see Oncogenes, Tumor Suppressor Genes, and DNA Repair Genes.

Chromosome and gene changes in CLL cells

CLL cells often have changes in many different genes that normally help control cell growth. These gene changes can vary from person to person.

Each human cell has 23 pairs of chromosomes. In most people with CLL, the CLL cells have a change in at least one of these chromosomes.

Most often the change is a deletion, which is a loss of part of a chromosome.

• The loss of part of chromosome 13 (written as del(13)) is the most common deletion. This can affect the cell’s ability to die when it should.
• The loss of part of chromosome 11 (written as del(11)) is the second most common. This results in the loss of the ATM gene, which is an important DNA repair gene.
• A deletion of part of chromosome 17 (written as del(17)) leads to the loss of  TP53, an important tumor suppressor gene inside cells.

Sometimes CLL cells have an extra chromosome 12 (trisomy 12). Many of the genes on this chromosome affect cell growth. Having an extra copy of these genes can lead to cells growing out of control.

While not all CLL cells have the same gene mutations, they all have changes in some genes that help control cell growth, often without an obvious chromosome change.

Some of the genes most often affected in CLL cells include:

• TP53
• ATM
• NOTCH1
• SF3B1

Many other genes that help control cell growth might be affected as well.

CLL cells and B lymphocytes (B cells)

CLL starts in early forms of B lymphocytes (B cells), which are part of the immune system. Scientists think that the way B cells normally work might contribute to why they sometimes become CLL cells.

B cells are programmed to start growing and dividing when they come into contact with a substance in the body called an antigen. (Antigens are substances like proteins that trigger an immune response in the body. For example, germs and abnormal cells in the body contain antigens.)

Scientists think CLL begins when B lymphocytes continue to divide without restraint after they have reacted to an antigen. But exactly why this happens is not yet known.

Are CLL gene mutations inherited from a parent?

Sometimes people inherit DNA (gene) mutations from a parent that greatly increase their risk of getting certain types of cancer.

Having a family member with CLL does increase a person’s risk of developing CLL, so there might be some gene changes passed on from a parent that affect this risk. But inherited gene mutations are not thought to play a large role in CLL, at least not in the same way they do in some other types of cancer.

DNA changes related to CLL usually happen during a person's lifetime, rather than being passed on from a parent. These acquired gene changes can build up inside cells over a person’s lifetime, which might help explain why CLL largely affects older people.