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Nat Immunol. 2015 Jul;16(7):766-74. doi: 10.1038/ni.3160. Epub 2015 May 18.

Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia.

Author information

1
Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA.
2
1] Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA. [2] University of Freiburg, Faculty of Biology, Freiburg, Germany.
3
1] Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA. [2] Department of Haematology, University of Cambridge, Cambridge, UK.
4
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
5
Centre for Evolution and Cancer, The Institute of Cancer Research, London UK.
6
University of Southern California, Los Angeles, California, USA.
7
Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
8
Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.
9
Genomics &Immunity, NIAMS, NIH, Bethesda, Maryland, USA.
10
Yale University, New Haven, Connecticut, USA.

Abstract

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.

PMID:
25985233
PMCID:
PMC4475638
DOI:
10.1038/ni.3160
[Indexed for MEDLINE]
Free PMC Article
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