Origins of chromosome translocations in childhood leukaemia

Key Points Different subtypes of leukaemia have distinctive chromosome translocations. Translocations seem to arise at the level of haematopoietic stem cells, but their impact is cell-context dependent, resulting in different effects in different lineages. Chromosome translocations are initiated by double-strand DNA breaks. The main repair mechanism underlying the resultant illegitimate recombination is probably non-homologous end-joining. The products of balanced chromosome translocations are fusion genes, generating either a dysregulated partner gene or a chimeric fusion protein with new properties (either altered transcriptional regulation or constitutive kinase activity). In childhood leukaemia, chromosome translocations arise mainly before birth during fetal haematopoiesis. Chromosome translocations can initiate leukaemogenesis, but are usually not sufficient, with additional postnatal events being required. The detailed understanding of chromosome translocations has implications for differential diagnosis, new therapies and molecular epidemiological studies that aim to uncover causality. Chromosome translocations are often early or initiating events in leukaemogenesis, occurring prenatally in most cases of childhood leukaemia. Although these genetic changes are necessary, they are usually not sufficient to cause leukaemia. How, when and where do translocations arise? And can these insights aid our understanding of the natural history, pathogenesis and causes of leukaemia?