Between 1973 and 1990, the number of acute lymphoblastic leukemia (ALL) cases in children under 15 increased by 27%. The causes of the disease and this dramatic rise remain unknown, but experts believe that ALL develops due to a combination of genetic and environmental factors.

Viruses are under investigation, along with approximately 75,000 new synthetic chemicals introduced in the first half of the century, emissions from cars, pesticides in food and residential areas, and runoff contaminants in drinking water.

Causes of acute lymphoblastic leukemia

Genetic factors

Several genetic mutations associated with ALL have been identified. A new study highlights a defective gene known as Ikaros, which regulates lymphocyte development and may be responsible for ALL in infants. About 20% of adults and 5% of children with ALL have a genetic abnormality known as the Philadelphia (Ph) chromosome.

Children with the Ph chromosome tend to develop a more severe form of ALL. However, this chromosome does not appear to be as harmful in most adults with ALL.

Around 20% of ALL patients have a genetic defect called TEL-AML1, which responds well to chemotherapy. Another defect, ETV6, also shows a good response to treatment.

Genetic abnormalities such as E2A-PBX1, MLL, and BCR-ABL may require aggressive therapy. In some cases of ALL, missing or defective tumor-suppressing genes contribute to disease development.

Up to 65% of leukemias involve genetic rearrangements, known as translocations, where genetic material is altered or exchanged between chromosomes. For example, t(12;21)—a translocation between chromosomes 12 and 21—is the most common genetic lesion in ALL, occurring in approximately 20% of patients. This translocation is associated with a favorable prognosis.

The t(4;11) translocation is most frequently observed in children under one year of age and is linked to a poor prognosis. Another translocation, t(9;22), also indicates a poor outlook. Around 30% of adults with the Philadelphia (Ph) chromosome also carry t(9;22), which significantly worsens their prognosis compared to those with ALL who do not have this translocation.

Environmental factors

Radiation

Ionizing radiation, such as X-rays and gamma rays, has enough energy to penetrate the human body and disrupt chemical bonds. Exposure to repeated or high doses of ionizing radiation increases the likelihood of developing leukemia.

Industrial and pharmaceutical chemicals

Certain chemicals are known to cause leukemia, with benzene being the most well-researched and widely recognized for its link to acute leukemia, particularly acute myeloid leukemia (AML). Some chemotherapy drugs used to treat other cancers—such as alkylating agents like melphalan (Alkeran) or platinum-based chemotherapies for ovarian cancer—also raise the risk of developing acute leukemia. Other drugs, including chloramphenicol and phenylbutazone, may further increase the risk.

A study investigating a town with a cluster of ALL cases noted its proximity to a large agricultural area where pesticides were heavily used.

Although no direct cause-and-effect relationship has been proven, another study in three Irish counties found that exposure to agricultural chemicals correlated with a higher incidence of chronic leukemia and non-Hodgkin’s disease, especially among farmers who did not wear protective masks while spraying pesticides.

Infections

Some experts suggest that certain cases of childhood ALL may arise due to an abnormal immune response to infections. Clusters of ALL cases have been observed in various small geographical areas, particularly regions with high rates of inward migration, suggesting a possible link between infections and disease onset.

A recent Swedish study supporting this theory found that childhood lymphoblastic leukemia was significantly more common in densely populated areas than in rural regions. Scientists have long known that special viruses, called retroviruses or RNA tumor viruses, can cause leukemia in animals. The first virus linked to leukemia in humans was human thymic leukemia virus-1 (HTLV-1), which may cause genetic changes that contribute to some cases of adult acute T-cell leukemia.

Additional risks

1. Other environmental risk factors

• Air Pollution & Industrial Toxins: A 2022 study found that prolonged exposure to fine particulate matter (PM2.5) and volatile organic compounds (VOCs) in industrial areas may contribute to leukemia risk, especially in urban settings.
• Household Chemicals: Some research suggests that exposure to household pesticides, disinfectants, and solvents used in home cleaning products may slightly increase the risk of childhood ALL.

2. Parental exposures & prenatal factors

• Maternal Smoking & Alcohol Consumption: Studies indicate that maternal smoking and alcohol use during pregnancy may slightly increase the likelihood of ALL in offspring.
• Paternal Occupational Exposures: Fathers exposed to pesticides, heavy metals, and radiation in their workplaces before conception have been linked to an increased risk of leukemia in their children.

3. Diet & nutritional factors

• Folate Deficiency During Pregnancy: Low maternal folate levels have been associated with a higher risk of ALL in children, possibly due to impaired DNA repair mechanisms.
• High Consumption of Processed Foods: Some studies suggest that diets rich in processed meats, artificial additives, and refined sugars may contribute to a pro-inflammatory state, which could promote leukemia development.

4. Viral infections & immunological factors

• Delayed Infection Hypothesis: A widely discussed theory suggests that children who grow up in highly sanitized environments may lack early immune system challenges, making them more susceptible to leukemia-triggering infections later in childhood.
• Epstein-Barr Virus (EBV) & ALL: Some studies propose that EBV, the virus responsible for mononucleosis, may play a role in certain cases of ALL, particularly in immunocompromised children.

5. Emerging research & future directions

• Genetic Predisposition & Polygenic Risk Scores: New research is exploring how multiple small genetic variations (rather than a single mutation) may collectively increase the risk of ALL.
• Targeted Therapies & Personalized Medicine: Advances in genetic profiling have led to the development of new treatments, such as CAR-T cell therapy, which is showing promise in treating relapsed or high-risk ALL cases.

Sources and publications:

1. https://kidshealth.org/en/parents/all.html
2. https://www.cancer.org/cancer/types/acute-lymphocytic-leukemia/causes-risks-prevention/risk-factors.html
3. https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia
4. https://www.mayoclinic.org/diseases-conditions/acute-lymphocytic-leukemia/symptoms-causes/syc-20369077
5. https://www.cancer.org/cancer/types/acute-lymphocytic-leukemia/causes-risks-prevention/what-causes.html
6. https://www.cancerresearchuk.org/about-cancer/acute-lymphoblastic-leukaemia-all/risks-causes
7. https://www.nhsinform.scot/illnesses-and-conditions/cancer/cancer-types-in-adults/acute-lymphoblastic-leukaemia/
8. https://www.lls.org/leukemia/acute-lymphoblastic-leukemia