Perspectives on the causes of childhood leukemia

Abstract

Acute leukemia is the most common cancer in children but the causes of the disease in the majority of cases are not known. About 80% are precursor-B cell in origin (CD19+, CD10+), and this immunophenotype has increased in incidence over the past several decades in the Western world. Part of this increase may be due to the introduction of new chemical exposures into the child's environment including parental smoking, pesticides, traffic fumes, paint and household chemicals. However, much of the increase in leukemia rates is likely linked to altered patterns of infection during early childhood development, mirroring causal pathways responsible for a similarly increased incidence of other childhood-diagnosed immune-related illnesses including allergy, asthma, and type 1 diabetes. Factors linked to childhood leukemia that are likely surrogates for immune stimulation include exposure to childcare settings, parity status and birth order, vaccination history, and population mixing. In case-control studies, acute lymphoblastic leukemia (ALL) is consistently inversely associated with greater exposure to infections, via daycare and later birth order. New evidence suggests also that children who contract leukemia may harbor a congenital defect in immune responder status, as indicated by lower levels of the immunosuppressive cytokine IL-10 at birth in children who grow up to contract leukemia, as well as higher need for clinical care for infections within the first year of life despite having lower levels of exposure to infections. One manifestation of this phenomenon may be leukemia clusters which tend to appear as a leukemia "outbreak" among populations with low herd immunity to a new infection. Critical answers to the etiology of childhood leukemia will require incorporating new tools into traditional epidemiologic approaches - including the classification of leukemia at a molecular scale, better exposure assessments at all points in a child's life, a comprehensive understanding of genetic risk factors, and an appraisal of the interplay between infectious exposures and the status of immune response in individuals.

Figure 1. Distribution of acute lymphoblastic leukemia subtypes by age

The figure demonstrates remarkable differences in the frequencies of cytogenetic features of leukemias by age.

Figure 2. Hematopoiesis

Blood cells are derived from multipotential progenitors. Nearly every cell noted here has a neoplastic counterpart which exhibits morphological features of its cell of origin. Those leukemia subtypes discussed extensively in the text are noted.

Figure 3. A model illustrating key events in the development of childhood acute lymphoblastic leukemia

Genetic events are shown above the horizontal line, and immune development below the line. Initiating mutations are quite common, perhaps in 1% of normal live births, but among these births a second mutation after birth in the same initiated cell is rare. Epidemiologic exposures linked to the initiating mutation are not well established but chemical causes are a possibility (Scelo paper cite). Occurrence of the secondary post-natal mutation is enhanced by features of immune development - namely, a higher propensity to overreact to common infections early in life, and a lower overall exposure to infections and other immune stimuli. Figure modeled after Figure 1, Greaves et al., 2006.