What Causes Acute Myeloid Leukemia (AML)?

Some people with acute myeloid leukemia (AML) have one or more known risk factors, but many do not. Even when a person has one or more risk factors, it's very hard to know if it actually caused the cancer.

Certain changes in the DNA in normal bone marrow cells can cause them to become leukemia cells. The DNA inside our cells makes up our genes, which control how our cells function. We tend to look like our parents because they are the source of our DNA. But our genes affect more than how we look.

Some genes control when our cells grow, divide to make new cells, and die at the right time:

• Genes that help cells grow, divide, or stay alive are called oncogenes.
• Genes that help keep cell division under control or make cells die at the right time are called tumor suppressor genes.

The DNA inside each cell is in long strands called chromosomes. Each time a cell divides into 2 new cells, it must make a new copy of its chromosomes. This process isn't perfect, and errors can occur that affect genes within the chromosomes. Cancers (including AML) can be caused by mutations (changes) that turn on oncogenes or turn off tumor suppressor genes. For instance, changes in certain genes such as FLT3, c-KIT, and RAS are common in AML cells. These types of changes can stop bone marrow cells from maturing the way they normally would, or help the cells grow out of control.

Mutations in many different genes can be found in AML, but larger changes in one or more chromosomes are also common. Even though these changes involve larger pieces of DNA, their effects are still likely to be due to changes in just one or a few genes that are on that part of the chromosome. Several types of chromosome changes may be found in AML cells:

• Translocations are the most common type of chromosome change. A translocation means that a part of one chromosome breaks off and becomes attached to a different chromosome. The point at which the break occurs can affect nearby genes – for example, it can turn on oncogenes or turn off genes like RUNX1 and RARa, which would normally help blood cells to mature.
• Deletionsoccur when part of a chromosome is lost. This can result in the cell losing a gene that helped keep its growth in check (a tumor suppressor gene).
• Inversions occur when part of a chromosome gets turned around, so it’s now in reverse order. This can result in the loss of a gene (or genes) because the cell can no longer read its instructions (much like trying to read a book backward).
• Addition or duplication means that there is an extra chromosome or part of a chromosome. This can lead to too many copies of certain genes within the cell. This can be a problem if one or more of these genes are oncogenes.

There are many types of AML, and different cases of AML can have different gene and chromosome changes, some of which are more common than others. Doctors are trying to figure out why these changes occur and how each of them might lead to leukemia. For example, some are more common in leukemia that occurs after chemotherapy for another cancer.

Some changes seem to have more of an effect on a person’s prognosis (outlook) than others. For instance, some changes might affect how quickly the leukemia cells grow, or how likely they are to respond to treatment. This is discussed in more detail in Acute Myeloid Leukemia (AML) Subtypes and Prognostic Factors.

Inherited versus acquired gene changes

Some people with certain types of cancer have inherited DNA mutations from a parent that increase their risk for the disease. Although this can happen sometimes with AML, such as with the genetic syndromes discussed in Risk Factors for Acute Myeloid Leukemia (AML), inherited mutations are not a common cause of AML.

Most DNA changes related to AML occur during a person’s lifetime, rather than having been inherited before birth. Some of these acquired changes may have outside causes like radiation or cancer-causing chemicals, but in most cases the reason they occur isn't clear. Many of these gene changes are probably just random events that sometimes happen inside a cell, without having an outside cause. They seem to happen more often as we age, which might help explain why AML usually occurs in older people.