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Childhood acute lymphoblastic leukemia (ALL) can often be traced to a pre-leukemic clone carrying a prenatal genetic lesion. Postnatally acquired mutations then drive clonal evolution toward overt leukemia. The enzymes RAG1-RAG2 and AID, which diversify immunoglobulin-encoding genes, are strictly segregated in developing cells during B lymphopoiesis and peripheral mature B cells, respectively. Here we identified small pre-BII cells as a natural subset with increased genetic vulnerability owing to concurrent activation of these enzymes. Consistent with epidemiological findings on childhood ALL etiology, susceptibility to genetic lesions during B lymphopoiesis at the transition from the large pre-BII cell stage to the small pre-BII cell stage was exacerbated by abnormal cytokine signaling and repetitive inflammatory stimuli. We demonstrated that AID and RAG1-RAG2 drove leukemic clonal evolution with repeated exposure to inflammatory stimuli, paralleling chronic infections in childhood.

http://www.nature.com/ni/journal/vaop/ncurrent/full/ni.3160.html

References

  1. Wiemels, J.L. et al. Prenatal origin of acute lymphoblastic leukaemia in children. Lancet 354, 1499–1503 (1999).

  2. Greaves, M.F. & Wiemels, J. Origins of chromosome translocations in childhood leukaemia. Nat. Rev. Cancer 3, 639–649 (2003)

  3. Bateman, C.M. et al. Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia. Blood 115, 3553–3558 (2010)

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