Acute Myeloid Leukemia (AML) is a rapidly progressing cancer of the blood and bone marrow, characterized by the uncontrolled growth of abnormal white blood cells (myeloblasts). While AML primarily affects older adults, it can occur at any age. The vast majority of AML cases are not inherited. However, a small minority (5% to 10%) are linked to specific inherited genetic changes, which confer an increased lifetime risk of developing AML.
Inherited Versus Acquired AML
The distinction between inherited and acquired AML rests on where and when the genetic mutation first occurs. Acquired, or somatic, AML is the most common form, arising from genetic changes that develop randomly in a blood stem cell during a person’s lifetime. These mutations are only present in the cancerous cells and cannot be passed down to children. Environmental factors or exposure to certain chemicals can sometimes contribute to these acquired changes, but often the cause is unclear.
Inherited, or germline, AML involves a genetic mutation that is present in every cell of the body, including the reproductive cells. This means the genetic change that increases cancer risk can be passed from a parent to a child. A person who inherits this germline mutation has an elevated susceptibility to developing AML compared to the general population. The leukemia then typically develops when a second, acquired mutation occurs later in life, interacting with the existing inherited change.
The inherited predisposition acts as a first “hit” on the DNA, making stem cells unstable and vulnerable to a second mutation. This two-step process explains why people with an inherited risk carry a heightened probability but do not necessarily develop the disease. The specific inherited gene change dictates the level of lifetime risk and the typical age of onset. Understanding the germline status of a mutation is important for family members and for informing treatment decisions.
Recognized Syndromes That Increase Risk
The risk of inherited AML is associated with two categories of genetic conditions: syndromes involving chromosomal instability and specific single-gene mutations. Syndromes like Fanconi Anemia and Bloom syndrome fall into the first category, elevating AML risk by impairing the body’s ability to repair damaged DNA. Individuals with these conditions have a generalized defect in genetic maintenance, leading to a higher chance of developing cancers, including AML and Myelodysplastic Syndrome (MDS).
The second category involves germline mutations in key transcription factor genes that directly regulate blood cell development. These mutations often lead to an increased risk of AML without the broader physical features seen in the chromosomal instability syndromes. Three of the most well-characterized genes in this group are RUNX1, GATA2, and CEBPA.
GATA2 and RUNX1 Mutations
Mutations in the GATA2 gene result in GATA2 deficiency, which is associated with immunodeficiency and a high risk of MDS or AML, often diagnosed around age 19. Similarly, germline RUNX1 mutations predispose individuals to familial platelet disorder and a propensity for AML, with an average age of onset around 29 years.
CEBPA Mutations
In contrast, CEBPA mutations often present solely as a high risk for AML, typically without a preceding diagnosis of MDS or other observable preleukemic features. The identification of these specific germline mutations has led to the formal recognition of “Myeloid Neoplasms with Germline Predisposition” in international classification systems.
Screening and Counseling for High-Risk Families
For families with a history of AML or a known germline mutation, genetic counseling is the first step. A genetic counselor assesses the specific family risk, interprets test results, and explains the inheritance patterns of the mutation. This process helps individuals understand their personal risk and the implications for other family members.
Genetic testing confirms the presence of a germline mutation. Since blood cells can be affected by leukemia, tests for germline status often use DNA extracted from a non-blood source, such as a skin biopsy or saliva sample. Advanced techniques like panel testing or whole-exome sequencing screen for mutations in known predisposition genes like RUNX1, GATA2, CEBPA, and DDX41.
For individuals identified as high-risk carriers, proactive steps are taken to manage the risk. This includes regular surveillance, such as frequent blood counts and periodic bone marrow screenings, to detect the earliest signs of leukemia or MDS. If a carrier requires a stem cell transplant, genetic testing of potential family donors is essential to ensure the donated cells do not carry the inherited predisposition mutation.