Leukemia is a cancer of the body’s blood-forming tissues, including the bone marrow and the lymphatic system. It is characterized by the rapid and uncontrolled production of abnormal white blood cells that interfere with the production of normal blood cells. While generally not inherited directly, leukemia is caused by genetic changes that occur during a person’s lifetime, involving both acquired DNA changes and rare inherited susceptibilities that increase risk.
The Role of Acquired Somatic Mutations
The vast majority of leukemia cases arise from acquired, or somatic, mutations, which are changes in the DNA of blood cells that occur after conception and are not passed down to offspring. These genetic errors happen during the normal process of cell division in the bone marrow, often as a result of errors in DNA replication or repair. When these somatic mutations affect genes that control cell growth, differentiation, or programmed cell death, they can disrupt the normal maturation of white blood cells.
These disruptions lead to the uncontrolled proliferation of abnormal cells that crowd out healthy blood components, defining the disease. One of the most common types of acquired genetic change seen in leukemia is the gene translocation, where parts of two different chromosomes break off and switch places. This rearrangement creates a fusion gene that produces an abnormal, constantly active protein that drives the cancerous growth.
The BCR-ABL fusion gene, for example, results from a translocation between chromosomes 9 and 22, and it is the defining genetic marker for Chronic Myeloid Leukemia (CML). Other acquired changes, such as specific deletions or duplications of genetic material, can also act as major disease drivers. These driver mutations are primary genetic events that initiate the transformation of a normal blood cell into a cancerous one.
Inherited Genetic Syndromes That Increase Risk
While the disease itself is rarely inherited, a small percentage of leukemia cases are linked to an inherited predisposition, meaning a person is born with a higher risk of developing the cancer. This increased susceptibility comes from germline mutations, which are present in every cell of the body and can be passed from parent to child. These inherited conditions elevate risk because the affected genes play roles in maintaining genetic stability, such as DNA repair or cell cycle regulation.
Individuals inheriting these specific genetic syndromes are less able to correct the spontaneous somatic mutations that naturally occur throughout life. Down syndrome, caused by an extra copy of chromosome 21 (Trisomy 21), is one of the most well-known examples, significantly increasing the risk for both Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL). Fanconi anemia is another inherited condition that severely impairs the body’s ability to repair damaged DNA strands.
These DNA repair deficiencies make hematopoietic stem cells highly vulnerable to accumulating the acquired mutations necessary to trigger leukemia. Li-Fraumeni syndrome, which involves an inherited mutation in the TP53 tumor suppressor gene, also increases the lifetime risk of developing various cancers, including leukemia. Recognizing these rare inherited syndromes is important for early screening and monitoring of at-risk family members.
Non-Genetic Environmental Triggers
External factors can interact with a person’s genetic profile to increase the likelihood of acquiring the somatic mutations that cause leukemia. These environmental triggers are considered mutagens, substances that directly damage the DNA within existing blood cells. They do not cause inherited changes but rather increase the rate at which acquired mutations accumulate.
High-dose ionizing radiation exposure is a documented risk factor, often linked to occupational hazards or prior therapeutic radiation treatments for other cancers. Exposure to specific industrial chemicals, most notably benzene, has been strongly associated with an elevated incidence of AML. Certain types of chemotherapy or immunosuppressive drugs used to treat other conditions can also induce secondary leukemias years later by causing widespread DNA damage.
How Genetic Information Guides Treatment and Prognosis
Once leukemia is diagnosed, comprehensive genetic profiling, or molecular testing, is performed on the cancer cells to identify the specific acquired mutations present. This detailed genetic information is used by doctors to determine the most effective and personalized course of action. Identifying specific fusion genes or mutations allows for the selection of highly precise targeted therapies.
Tyrosine Kinase Inhibitors (TKIs) are a prime example of this application, as they are drugs specifically designed to block the abnormal protein activity produced by the BCR-ABL fusion gene in CML. This approach avoids the widespread toxicity associated with traditional chemotherapy by precisely targeting the mechanism driving the cancer. Genetic markers are also used for risk stratification, providing important prognostic information.
Certain mutations, such as those involving the FLT3 gene or the TP53 tumor suppressor, are often associated with a less favorable prognosis, prompting doctors to pursue more intensive treatment regimens. Conversely, some gene profiles are linked to better outcomes and may allow for less aggressive therapy. Genetic sequencing is also used to monitor for Minimal Residual Disease (MRD) after treatment. Detecting minute amounts of residual cancerous DNA can signal a potential relapse, allowing for timely therapeutic intervention.