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.

Figure 1

a. Immunophenotype screens in the 1970’s and early 1980’s established that ALL could be divided into subsets corresponding to early developmental compartments of the B and T cell lineages, as indicated in the key Common or B cell precursor ALL (BCP-ALL) is genetically diverse (as illustrated) with the two most prevalent alterations being ETV6-RUNX1 fusion and hyperdiploidy. The rare (~2%) subtype with a mature B cell immunophenotype (and frequent IGH-MYC rearrangements) was subsequently recognised (and treated) not as ALL but as B lymphoblastic lymphoma. For more detailed descriptions of genomic diversity in ALL, see references ^–. b. Age distribution of ALL subtypes from a cohort of 1184 patients with ALL entered into MRC-UKALL clinical trials (1975-1984). This pattern of age-associated ALL subtypes was validated in a later cohort of MRC-UKALL trials (1991-1996; 1088 patients up to 14 years of age) It had been known that childhood ALL had a very marked age incidence peak at 2-5 years throughout the developed world. But this peak appeared to be diminished or absent in less developed societies and appeared in particular countries and ethnic groups at different times . Immunophenotypic screens, linked to clinical trials in the UK , and an international collaborative group study documented that the peak in incidence was selectively common or BCP-ALL. Recent epidemiological data indicates that the incidence of this subtype of leukaemia in Europe has continued to increase at around 1% per year ^–. This suggested that the increase over time could be real, rather than ascertainment bias, and that BCP-ALL might have had a distinctive aetiology. The BCP-ALL subtype was also found to have a much more favourable clinical outcome ^,,, emphasizing its distinct biology. Modified with permission from ref .

Figure 2

Summary of comparative genomics of ALL in identical twin pairs. The figure is based on analysis of 12 monozygotic twin pairs (the number of pairs with each founder lesion is noted in parentheses) with concordant ALL ^,,,,. The sharing of a patient- and clone-specific fusion gene that is not inherited in the twins indicates that in such cases of concordant ALL, the leukaemia must have been initiated in a single cell, in one twin of the pair in utero, the clonal progeny of that cell then disseminating to the co-twin, via intra-placental anastomoses. In further support of this notion, it was noted that concordance of ALL only occurred where the twins shared a single or monochorionic placenta, providing a route for cellular transmission . Figure adapted from reference . CNAs, copy number alterations. SNVs, single nucleotide variants.

Figure 3

Summary of 2 hit model for role of infections in B cell precursor ALL. Genetic, inherited risk alleles are depicted (top of figure) as impacting at any or several stages of the step-wise process of ALL.