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- Title
Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia.
- Authors
Swaminathan, Srividya; Klemm, Lars; Park, Eugene; Papaemmanuil, Elli; Ford, Anthony; Kweon, Soo-Mi; Trageser, Daniel; Hasselfeld, Brian; Henke, Nadine; Mooster, Jana; Geng, Huimin; Schwarz, Klaus; Kogan, Scott C; Casellas, Rafael; Schatz, David G; Lieber, Michael R; Greaves, Mel F; Müschen, Markus
- 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.
- Subjects
LYMPHOBLASTIC leukemia; JUVENILE diseases; SOMATIC mutation; ENZYMES; B cells; ETIOLOGY of diseases
- Publication
Nature Immunology, 2015, Vol 16, Issue 7, p766
- ISSN
1529-2908
- Publication type
Article
- DOI
10.1038/ni.3160