Acute myeloid leukemia: Causes and risk factors explained
Fact-checked by Acute myeloid leukemia (AML) is a type of blood cancer that develops when genetic changes cause immature blood cells to grow uncontrollably in the bone marrow, the spongy tissue inside bones where most blood cells are produced.
There is no single explanation for why these genetic changes occur, and many AML cases have no obvious cause. However, researchers have identified several factors, such as genetic conditions, certain blood disorders, smoking, and previous cancer treatment, that may increase a person’s likelihood of developing the disease.
Because many AML risk factors cannot be avoided, the disease is difficult to prevent. Still, understanding AML causes and risk factors may help identify people at risk who could benefit from closer monitoring.
Once AML develops, understanding the genetic changes driving the disease can also help doctors estimate how the leukemia is likely to behave and to select the most appropriate treatment.
How does AML develop?
Researchers are still working to understand what causes leukemia, but it’s well established that it occurs when genetic mutations disrupt the production of blood cells in the bone marrow.
AML develops when immature cells that would normally give rise to red blood cells, platelets, and certain white blood cells — collectively known as myeloid cells — start to multiply uncontrollably in the bone marrow instead of maturing into healthy blood cells.
Unlike mature white blood cells, these immature cells, called blasts, don’t have fully developed immune properties. They can also replicate quite quickly, which provides more opportunities for additional mutations to accumulate over time and perpetuate the disease.
As blasts continue to divide and grow, they begin to crowd the bone marrow, which interferes with the production of normal red blood cells, white blood cells, and platelets, the tiny fragments that help blood to clot. This shortage of healthy blood cells, together with the buildup of leukemia cells in the blood and bone marrow, causes many of the symptoms of AML.
Genetic factors
Genetic mutations linked to AML may be inherited from a person’s biological parents or acquired during life. Advances in genetic sequencing suggest that approximately 10% to 15% of AML cases involve inherited genetic predisposition, though most appear to result from acquired mutations that develop with aging or environmental exposures.
Several inherited conditions increase the risk of developing AML. These include:
- ataxia-telangiectasia
- Bloom syndrome
- Diamond-Blackfan anemia
- Down syndrome
- Fanconi anemia
- Li-Fraumeni syndrome
- neurofibromatosis type 1
- severe congenital neutropenia
- Shwachman-Diamond syndrome
- trisomy 8
In addition to the genetic abnormalities causing these inherited conditions, many other genetic mutations have been linked to AML development. Some of these mutations are also associated with different forms of AML and can influence how the disease behaves after it develops.
For example, mutations in the NPM1 gene, which are found in about one-third of AML patients, are generally associated with a more favorable prognosis, while mutations in the KMT2A gene are often linked to a highly aggressive disease that’s resistant to standard treatments and has a high relapse rate.
Preexisting conditions
Certain blood disorders and other medical conditions can also increase the risk of AML.
For example, some blood disorders can progress to AML over time, including:
- Myelodysplastic syndrome (MDS): In this group of disorders, blood stem cells fail to mature into healthy blood cells. People with high-risk or very high-risk MDS are especially likely to develop AML, making regular monitoring important.
- Myeloproliferative neoplasms: This group of chronic blood cancers occurs when the bone marrow produces too many blood cells. Among these cancers are primary myelofibrosis, essential thrombocythemia, and polycythemia vera, all of which can, in some cases, progress to AML.
- Chronic myeloid leukemia: This slow-growing blood cancer can sometimes transform into acute leukemia.
Some autoimmune conditions have also been linked to a higher risk of AML. These include:
- rheumatoid arthritis
- autoimmune hemolytic anemia
- ulcerative colitis
It isn’t yet clear whether the conditions themselves or their treatment, which often includes long-term immunosuppression, contribute to this risk.
Environmental factors
Exposure to certain environmental substances can also increase the risk of developing AML. In general, the risk is greatest after prolonged exposure or following a brief but intense exposure.
Unlike inherited genetic factors or some preexisting medical conditions, several of these environmental leukemia risks are potentially modifiable. This means that reducing or avoiding exposure to those substances may help lower a person’s risk of developing the disease.
Some environmental factors linked to AML include:
- exposure to certain chemotherapy drugs or radiation therapy for a previous cancer
- exposure to high doses of radiation
- smoking
- exposure to harmful chemicals, such as benzene
Exposure to certain substances, including those used as treatments for other types of cancer, has been linked to AML and other leukemias. These environmental leukemia risks tend to have stronger effects with prolonged exposure or with a brief but intense exposure.
Cancer treatment
Some people may develop AML after receiving treatment for another cancer, in which case it is known as therapy-related AML. Treatments associated with this risk include:
- Alkylating agents: This class of chemotherapy drugs damages the DNA of rapidly dividing cells to stop cancer growth. When AML develops after treatment with alkylating agents, it is often preceded by MDS.
- Topoisomerase II inhibitors: Another class of chemotherapy drugs, these therapies block an enzyme needed for DNA replication and cell division. AML associated with these drugs usually develops without a preceding MDS diagnosis.
- Radiation therapy: Using radiation treats cancer by damaging the DNA of cancer cells.
While these approaches are effective at treating cancers, they can also damage healthy cells and cause mutations that make people more prone to developing AML. However, it is important to note that, although some cancer treatments can increase the risk of developing AML later in life, the benefits of treating the original cancer far outweigh this risk.
Radiation exposure
Exposure to high levels of radiation outside of cancer treatment, such as from an atomic bomb or a nuclear reactor accident, may also increase the risk of cancers, including AML.
Some medical imaging tests also expose patients to small amounts of radiation, but whether low-dose exposures meaningfully increase AML risk remains uncertain.
Smoking
Smoking is a well-established risk factor for many cancers, including AML. The risk increases with long-term tobacco use.
Exposure to harmful chemicals
Exposure to certain chemicals, either during work activities or hobbies, can also increase the risk of AML. One example is benzene, an industrial solvent that can contribute to AML with long-term exposure.
People working in certain industries or who are regularly in close contact with certain benzene-containing products are more likely to incur this type of risk. Some types of products that can include benzene are:
- cigarette smoke
- gasoline
- motor vehicle exhaust
- glues
- cleaning products
- detergents
- art supplies
- paints
Demographic factors
In addition to genetic, medical, and environmental risk factors, researchers have identified several demographic characteristics that are associated with a person’s likelihood of developing AML.
While these factors do not directly cause the disease, they can influence how often AML occurs in different groups of people and help doctors better understand who is at greater risk.
Demographic factors associated with an increased risk of AML include:
- Sex: AML is slightly more common in men and boys than women and girls, with an estimated male-to-female ratio of 5:3.
- Age: The risk of AML increases with age, and the median age at diagnosis is approximately 68.
- Race and ethnicity: AML is diagnosed more frequently in non-Hispanic white people than among those in other racial and ethnic groups.
- Family history: Having a close relative with AML is associated with an increased risk, although most people diagnosed with AML have no family history of the disease.
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