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  • Review Article
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A causal mechanism for childhood acute lymphoblastic leukaemia

Nature Reviews Cancer volume 18, pages 471–484 (2018)Cite this article

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An Author Correction to this article was published on 30 May 2018

This article has been updated

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.

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Fig. 1: Major subtypes of childhood ALL.
Fig. 2: Summary of comparative genomics of ALL in identical twin pairs.
Fig. 3: Summary of the two-hit model for role of infections in B cell precursor ALL.

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Change history

  • 30 May 2018

    The article as originally published cited the incorrect paper as reference 123. The correct reference is Kroll, M. E., Draper, G. J., Stiller, C. A. & Murphy, M. F. G. Childhood leukemia incidence in Britain, 1974–2000: time trends and possible relation to influenza epidemics. J. Natl Cancer Inst. 98, 417–420 (2006). This has been corrected in the online and print versions of the article.

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Acknowledgements

The author thanks the Leukaemia Research Fund UK (now Bloodwise), The Kay Kendall Leukaemia Fund, the Wellcome Trust [105104/Z/14/Z] and The Institute of Cancer Research, London, for long-term funding support. The author also thanks R. Houlston for constructive comments on the manuscript. The author is indebted to many students and postdoctoral fellows in his laboratory who have researched this topic over many years and to the many scientists and clinicians who have been excellent collaborators. These include A. Ford, J. Wiemels, A. T. Maia, L. C. Chan, C. Bateman, D. Alpar, I. Titley, S. Colman, H. Mori, V. Cazzaniga, K. Anderson, N. Potter, L. Kearney and R. Houlston (all at The Institute of Cancer Research, London), as well as A. Lister, T. Eden, J. Chessells, P. Ancliff, R. Jarrett, A. Borkhardt, P. Buffler, E. Roman, G. Cazzaniga, M. E. Cabrera, M. P. de Oliveira, A. Biondi, J. Kersey, M. Müschen, P. Campbell, E. Papaemmanuil and T. Enver.

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Nature Reviews Cancer thanks K. Paulsson, S. Sallan and J. Wiemels for their contribution to the peer review of this work.

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    Mel Greaves

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M.G. researched data for the article and wrote, reviewed and edited the manuscript.

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Glossary

Vascular anastomoses

Interconnected blood vessels (venous or arterial) in a twin, monochorionic placenta that facilitate the transfer of blood cells and fluids between identical twins.

Blood cell chimerism

The sharing of blood cells in monozygotic twins that developed in a single, or monochorionic, placenta.

Neonatal blood spots

Also known as Guthrie cards, these are samples of dried blood collected from a newborn baby shortly after birth via a heel prick that are routinely used to detect genetic conditions.

Non-homologous end joining via microhomologies

A common (error-prone) recombination method that cells use to repair double-stranded DNA breaks without a sequence template that often involves the use of microhomologies of a few bases in pairing DNA strands.

Space–time clusters

A set of patients diagnosed in a short time frame and resident in the same, small area.

Relative risk

(RR). The calculated increase in diagnoses in a group of patients expressed, proportionally, in relation to that expected in the general, age-matched population.

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Greaves, M. A causal mechanism for childhood acute lymphoblastic leukaemia. Nat Rev Cancer 18, 471–484 (2018). https://doi.org/10.1038/s41568-018-0015-6

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