Toward prevention of childhood ALL by early-life immune training

Abstract

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common form of childhood cancer. Chemotherapy is associated with life-long health sequelae and fails in ∼20% of cases. Thus, prevention of leukemia would be preferable to treatment. Childhood leukemia frequently starts before birth, during fetal hematopoiesis. A first genetic hit (eg, the ETV6-RUNX1 gene fusion) leads to the expansion of preleukemic B-cell clones, which are detectable in healthy newborn cord blood (up to 5%). These preleukemic clones give rise to clinically overt leukemia in only ∼0.2% of carriers. Experimental evidence suggests that a major driver of conversion from the preleukemic to the leukemic state is exposure to immune challenges. Novel insights have shed light on immune host responses and how they shape the complex interplay between (1) inherited or acquired genetic predispositions, (2) exposure to infection, and (3) abnormal cytokine release from immunologically untrained cells. Here, we integrate the recently emerging concept of "trained immunity" into existing models of childhood BCP-ALL and suggest future avenues toward leukemia prevention.

Graphical abstract

Figure 1.

Contribution of trained immune responses to BCP-ALL development. Children genetically predisposed to BCP-ALL harbor clonally expanded preleukemic cells at birth. A hematopoietic stressor, such as infection, has the potential to trigger ALL at a later time point (2-6 years). The genetically determined immune responses, cytokine release, and basal cytokine levels, especially of interferons, may influence the outgrowth of the leukemic clone. However, the role of earlier-trained innate cells in the control of the preleukemic clone is largely unappreciated thus far. Epidemiological and experimental data suggest that innate immunity can be trained by BCG vaccination or β-glucan application, which substantially reduces the risk of developing BCP-ALL.

Figure 2.

Possible preventive measures and proposed interventions that can help to reduce the risk of BCP-ALL development in genetically predisposed children. Before birth, maternal uptake of folic acid and a healthy diet (brown) have been associated with a reduced risk of BCP-ALL development. Maternal infection in pregnancy is associated with a significantly increased BCP-ALL risk related to viral transmission. After birth, trained immunity (green) and microbiome diversity (yellow) are important factors supported by epidemiological (filled bars) or experimental (striped bars) evidence. Immunity can be trained through vaccinations (TIBVs) before the age of 3 months, by breastfeeding and by social and livestock contacts (including pets) in the first year of life. Microbiome diversity is supported by a natural delivery and gradually builds up after birth. Again, breastfeeding and social and livestock contacts in the first year of life also have a beneficial impact on gut microbial diversity. Although only demonstrated in experimental models, the avoidance of overuse of antibiotics, the application of probiotics and a diet consisting of microbiome-supportive fibers are interventions that could also reduce the risk of leukemia development. Exposure of parents and children to various harmful chemicals can influence the microbiome along with carcinogenic effects. Further evidence needs to be generated through large population-based studies to identify preventive measures and to substantiate initial data on vaginal seeding and fecal transplants.

Figure 3.

Antibiotic treatment in the development of lymphoblastic leukemia. Antibiotic treatment in early life induces leukemia in genetically predisposed Pax5^+/− mice. (Left) In wild-type mice, depletion of the gut microbiome bacteria by antibiotic treatment at 8 weeks of age has only a transient effect on the immune system (including the gut-associated and peripheral lymphoid tissues) and mice do not develop pB-ALL. (Right) Pax5 heterozygosity directly affects B-cell maturation and leads to clonal hematopoiesis, while also indirectly reducing gut microbiota diversity. In response to bacterial depletion in the gut microbiome by antibiotic treatment at 8 weeks of age, the microbiome reconstitutes with further reduced diversity. Cooperating oncogenic mutations then lead to pB-ALL in ∼50% of these mice between 11 and 21 months of age. Leukemia development is preceded by a reduction of mature B and T cells in the gut and associated peripheral lymphoid tissues. However, it has not been tested in this model whether leukemia development can be inhibited through intervention. In addition to microbial dysbiosis, infectious stimuli can also cooperate with oncogenic mutations, leading to leukemia development in Pax5^+/− mice.