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

While we still 诲辞苍’迟 know what causes CML in most people, researchers are beginning to understand how changes in the DNA in certain bone marrow cells may cause CML to develop.

• We do know: CML happens when the DNA in a person’s bone marrow cells changes (mutates) and creates the BCR::ABL1 fusion gene.
• We 诲辞苍’迟 know: Exactly what causes the mutation in most people.

Learn more about these gene changes and what we know so far about their cause.

Changes in genes and chromosomes can lead to cancer

Cancer (including CML) 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. Each human cell has 23 pairs of chromosomes, one of which comes from each parent.

Our DNA 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. The BCR::ABL1 fusion gene responsible for CML is an oncogene.
• 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 CML cells

For most types of cancer, several genes must change (mutate) before normal cells become cancer cells. But CML is unusual. There is only one major gene change that leads to early forms of bone marrow cells becoming CML cells.

The Philadelphia chromosome and BCR::ABL1 gene

In CML cells, chromosomes 9 and 22 have swapped parts of their DNA. This type of chromosome change is known as a translocation. It happens during a mistake while a cell is dividing to make new cells.

Part of chromosome 9 goes to chromosome 22, and part of chromosome 22 goes to chromosome 9. The result is a chromosome 22 that's shorter than normal. This is known as the Philadelphia chromosome.

This swapping of DNA between chromosomes puts two genes next to each other (on the Philadelphia chromosome) that normally aren’t on the same chromosome. When this happens:

• A new gene (an oncogene) is formed. This new gene is called BCR::ABL1 (or BCR-ABL).
• The BCR::ABL1 gene tells the cell to make a new protein, also called BCR::ABL1 (or BCR-ABL).

The BCR::ABL1 protein is a type of tyrosine kinase.

A tyrosine kinase is an enzyme that helps send signals within a cell, such as to grow or stay alive. These types of proteins are normally regulated tightly, so they’re only active when they’re needed. But the BCR::ABL1 protein is always switched on, so it’s constantly telling CML cells to grow and stay alive.

What causes the BCR::ABL1 gene mutation?

It’s not clear what causes the Philadelphia chromosome (and the resulting BCR::ABL1 gene mutation) in most people.

Sometimes people inherit gene mutations from a parent that greatly increase their risk of getting certain types of cancer. But the BCR::ABL1 gene mutation is not inherited (passed on from parent to child before birth). Instead, it happens during a person's lifetime.

The only known environmental risk factor for CML is exposure to high-dose radiation. But this is thought to affect only a very small number of people with CML.

In most people with CML, this gene change is probably just a random event that sometimes happens inside a cell, without having an outside cause. These types of events seem to happen more often as we age, which might help explain why CML usually occurs in older people.

Other gene and chromosome changes in CML cells

The BCR::ABL1 gene mutation is the main change in CML cells, but other gene changes can also happen in the cells over time. These changes can lead to the CML cells growing faster and the CML progressing to a new phase.

Some examples of possible gene changes include:

• Loss of the TP53 tumor suppressor gene on chromosome 17
• Loss of chromosome 9
• Extra copies of chromosome 8 (trisomy 8) or 19 (trisomy 19)