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Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia. 2015
Srividya Swaminathan, and
Lars Klemm, and
Eugene Park, and
Elli Papaemmanuil, and
Anthony Ford, and
Soo-Mi Kweon, and
Daniel Trageser, and
Brian Hasselfeld, and
Nadine Henke, and
Jana Mooster, and
Huimin Geng, and
Klaus Schwarz, and
Scott C Kogan, and
Rafael Casellas, and
David G Schatz, and
Michael R Lieber, and
Mel F Greaves, and
Markus Müschen
Department of Laboratory Medicine, University of California San Francisco, CA, 94143.
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.
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