A causal mechanism for childhood acute lymphoblastic leukaemia

Abstract

In this Review, I present evidence supporting a multifactorial causation of childhood acute lymphoblastic leukaemia (ALL), a major subtype of paediatric cancer. ALL evolves in two discrete steps. First, in utero initiation by fusion gene formation or hyperdiploidy generates a covert, pre-leukaemic clone. Second, in a small fraction of these cases, the postnatal acquisition of secondary genetic changes (primarily V(D)J recombination-activating protein (RAG) and activation-induced cytidine deaminase (AID)-driven copy number alterations in the case of ETS translocation variant 6 (ETV6)-runt-related transcription factor 1 (RUNX1) ALL) drives conversion to overt leukaemia. Epidemiological and modelling studies endorse a dual role for common infections. Microbial exposures earlier in life are protective but, in their absence, later infections trigger the critical secondary mutations. Risk is further modified by inherited genetics, chance and, probably, diet. Childhood ALL can be viewed as a paradoxical consequence of progress in modern societies, where behavioural changes have restrained early microbial exposure. This engenders an evolutionary mismatch between historical adaptations of the immune system and contemporary lifestyles. Childhood ALL may be a preventable cancer.

Parental occupational exposure to pesticides, animals and organic dust and risk of childhood leukemia and central nervous system tumors: Findings from the International Childhood Cancer Cohort Consortium (I4C)

“…Organic dusts are complex mixtures containing microbes, allergens and other plant and animal material. Early life exposure to these agents through the para‐occupational route of exposure may be relevant since microbial exposures in early life and surrogates of those exposures such as later birth order and early daycare attendance have been hypothesized to show an inverse association with childhood ALL …”

Impact of Historic Migrations and Evolutionary Processes on Human Immunity

“…Moreover, reduced exposure to infectious agents can have a much wider effect than initially believed. Lack of exposure to microbes in childhood can cause aberrant responses to infection and potentiate the effects of ETV6-RUNX1 mutations in the pathogenesis of acute lymphoblastic leukemia [77]. By contrast, a meta-analysis of six observational studies, including 1902 participants, showed a correlation between low Helicobacter pylori infection and MS, suggesting that low H. pylori prevalence might be a putative protective factor in MS, although this remains to be experimentally validated [78].…”

Analytic Philosophy for Biomedical Research: The Imperative of Applying Yesterday’s Timeless Messages to Today’s Impasses

“…Moreover, among human cancers, one can point to successful primary treatments of lymphomas and leukemias (see, e.g., refs. [5,6]) and to overall "annual reductions of 1 to 2% in age-adjusted cancer mortality rates in the United States for many years" [7]. Relatedly, "childhood cancer was once a death sentence, but today more than 80% of children and teenagers survive long term", with the important caveat that "adults who survive cancer as children can suffer long-term health effects" [8].…”