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 approximately 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 (e.g. the ETV6-RUNX1 gene fusion) leads to the expansion of pre-leukemic B-cell clones, which are detectable in healthy newborn cord blood (up to 5%). These pre-leukemic clones give rise to clinically overt leukemia in only about 0.2% of carriers. Experimental evidence suggests that a major driver of conversion from the pre-leukemic 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 (A) inherited or acquired genetic predispositions, (B) exposure to infection, and (C) 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 towards leukemia prevention.

Risk Factors for Childhood Leukemia: Radiation and Beyond

“…Both hypotheses propose that ALL is a consequence of an abnormal response to common infections. Currently, three additional models of ALL evolution exist, which also point to infection-induced immune disturbances as being responsible for leukemia evolution as recently summarized by Hauer et al (65). A more detailed view into the role of infections is given elsewhere (17, 66, 67).…”

“…The observation that predisposed mice with a depleted gut microbiota developed leukemia, even without infectious stimuli, suggests that an intact gut microbiome protects genetically predisposed mice from developing pB-ALL (82). This protective effect is likely mediated through the release of microbial components or metabolites, or direct microbial binding to Toll-like receptors on innate immune cells (65,67).…”

“…Taken together, the role of infections as risk factor in the etiology of ALL, specifically pB-ALL, has strengthened considerably since the last research recommendations in 2014 (7), with the strongest support coming from the Pax5 +/− and Sca1-ETV6-RUNX1 mouse models. Therefore, training the immune system early in life could potentially help to prevent leukemia development and several epidemiological studies demonstrate that proxies for infectious agents or immune challenges early in life reduce the risk of ALL (65). Questions remain to be clarified regarding the time window in which infections are relevant, the specific infectious pathogen or pathogens that are involved (if any single given microbe could in fact be responsible) as well as the mechanism(s) and pathway(s) by which infections drive -or protect against -ALL development.…”

The Microbiome in Childhood Acute Lymphoblastic Leukemia

“…Microbial composition is well adjusted to the specific conditions in different areas of the human body, depending on age, environmental lifestyle, antibiotic therapy, and diet. The symbiotic interplay between host and bacteria results in a healthy mucosa, which offers protection from overt pathogens and provides nutrients, such as short fatty acids and branched-chain amino acids, as well as the production of glycans and lactic acids (Table 1) [14][15][16][17][18][19][20]. Furthermore, the microbiome shapes and influences the immune system in a positive way by inducing innate and adaptive immune responses [4].…”

“…Furthermore, the microbiome shapes and influences the immune system in a positive way by inducing innate and adaptive immune responses [4]. Studies have further revealed a profound impact on the early development of the innate immune system, referred to as trained immunity [15].…”