Acute myeloid leukemia (AML) results from DNA damage in blood-forming stem cells in the bone marrow, but no single cause explains most cases. The median age at diagnosis is 70, and over 60% of new cases occur in people aged 65 and older. For many patients, the triggering event is never identified. What researchers do know is that a combination of acquired genetic mutations, environmental exposures, prior cancer treatments, inherited predispositions, and precursor blood disorders can all set the stage for AML to develop.
How AML Develops in Bone Marrow
Bone marrow constantly produces new blood cells from a small pool of stem cells. These stem cells go through a step-by-step maturation process, eventually becoming functional red blood cells, white blood cells, or platelets. In AML, mutations in a stem cell create abnormal proteins that disrupt this process. The damaged cell gets stuck partway through maturation and keeps dividing without ever becoming a working blood cell.
These immature cells, called blasts, accumulate rapidly in the marrow and spill into the bloodstream. Because they crowd out normal blood cell production, the result is a shortage of healthy white blood cells (increasing infection risk), red blood cells (causing anemia), and platelets (leading to easy bleeding or bruising). The specific mutation involved shapes which subtype of AML a person has, how aggressively it behaves, and which treatments are most effective.
Acquired Genetic Mutations
Most cases of AML are driven by mutations that a person acquires during their lifetime rather than inherits from a parent. These mutations accumulate in bone marrow stem cells over decades, which is a major reason AML is so strongly linked to aging. Only 4% of cases occur in people under 20, while nearly 27% are diagnosed between ages 65 and 74.
Some of the most important mutations involve genes called NPM1 and CEBPA, which normally help regulate how stem cells mature. Others affect genes like TP53, ASXL1, and RUNX1, which act as quality-control checkpoints for cell growth. When these checkpoints fail, damaged cells survive and multiply instead of being eliminated. In many cases, a person accumulates several of these mutations before one final change tips the balance and triggers full-blown leukemia.
Another category involves chromosomal rearrangements, where large chunks of DNA break off and reattach in the wrong place. These rearrangements can fuse two genes together, producing an abnormal protein that jams the maturation process. One well-known example occurs in acute promyelocytic leukemia, a subtype of AML where a specific chromosomal swap creates a protein that locks cells in an immature state.
Prior Cancer Treatment
Previous chemotherapy or radiation therapy is one of the most clearly established causes, accounting for 10 to 20% of all AML cases. Drugs that work by directly damaging DNA, particularly a class called alkylating agents, increase the risk of AML by 100 to 1,000 times more than they increase the risk of other blood cancers. Radiation therapy also raises risk in a dose-dependent way: exposure equivalent to about 1 gray roughly doubles the likelihood of developing AML.
The time between cancer treatment and the appearance of AML varies. After some treatments, such as radioactive iodine used for thyroid cancer, the median lag is under three years. After conventional chemotherapy, the latency period tends to be longer, often five to seven years. This is why cancer survivors are monitored with blood tests for years after treatment ends. Treatment-related AML tends to carry more complex genetic abnormalities and can be more difficult to treat than AML that arises on its own.
Chemical and Environmental Exposures
Benzene is the best-documented environmental cause of AML. It is found in gasoline, industrial solvents, and cigarette smoke. Occupational exposure standards in the United States have dropped dramatically, from a permissible 8-hour average of 100 parts per million in 1941 to 0.5 parts per million since 1997, largely because of the established cancer risk. Workers in petroleum refining, rubber manufacturing, and shoe production historically faced the highest exposures.
Cigarette smoking carries a modest but real association with AML. Overall, smokers have roughly a 20% higher risk compared to nonsmokers. The link is stronger for certain subtypes and in older adults: smokers aged 60 to 75 had more than three times the risk for one particular AML subtype compared to nonsmokers of the same age. Benzene in tobacco smoke is thought to be a key contributor, along with other carcinogens that damage bone marrow DNA.
Inherited Genetic Conditions
A smaller but important fraction of AML cases trace back to inherited gene mutations that a person is born with. These are called germline mutations, meaning they exist in every cell in the body rather than arising only in the bone marrow.
One of the most significant is a mutation in the GATA2 gene. Up to 75% of people carrying a GATA2 alteration eventually develop a myeloid blood cancer, including AML. GATA2 deficiency is also one of the most common inherited causes of a precursor condition called myelodysplastic syndrome in children. Mutations in another gene, RUNX1, carry an estimated 40% lifetime risk of blood malignancy. People with RUNX1 mutations often have low platelet counts or bleeding problems years before any leukemia appears, which can serve as an early warning sign.
Several broader inherited syndromes also raise AML risk. Li-Fraumeni syndrome, caused by TP53 mutations, predisposes people to many cancers including AML. Fanconi anemia, Down syndrome, and other bone marrow failure disorders carry elevated risk as well. Some inherited mutations, like those in the DDX41 gene, don’t cause obvious symptoms beforehand and may not trigger disease until the sixth decade of life or later, making them easy to miss without genetic testing.
Precursor Blood Disorders
AML sometimes develops as the final stage of another blood disorder that has been slowly worsening. Myelodysplastic syndromes (MDS), a group of conditions where the bone marrow produces abnormal blood cells, are the most common precursor. Historically, 30 to 40% of MDS patients eventually progress to AML. Even among patients initially classified as low-risk MDS, about 9% progress directly to AML and another 6.5% progress through an intermediate high-risk stage before reaching AML.
Other blood disorders that can transform into AML include myeloproliferative neoplasms, conditions where the marrow overproduces certain blood cell types. Polycythemia vera and myelofibrosis both carry a recognized risk of AML transformation, particularly after many years of disease or after treatment with certain therapies. When AML arises from a pre-existing blood disorder, it typically carries genetic changes associated with worse outcomes, including complex chromosomal rearrangements and mutations in genes like TP53 and ASXL1.
Age and Cumulative DNA Damage
Age is the single strongest risk factor. The numbers are striking: fewer than 10% of AML cases occur before age 35, while more than 62% occur after age 65. This pattern reflects the nature of how AML develops. Each time a bone marrow stem cell divides, there is a small chance of acquiring a new mutation. Over decades, these mutations accumulate. By the time a person reaches their 60s or 70s, some stem cells may carry enough mutations that one additional change can push them toward leukemia.
A phenomenon called clonal hematopoiesis illustrates this process. As people age, it becomes increasingly common for a single mutated stem cell to expand and produce a disproportionate share of blood cells. This is detectable in blood tests of many healthy older adults and, while it does not mean leukemia is inevitable, it represents an intermediate state where the marrow is more vulnerable to further mutations that could lead to AML.