1. Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia
- Author
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Brian Hasselfeld, Srividya Swaminathan, Anthony M. Ford, Lars Klemm, Jana Mooster, Eugene Park, Huimin Geng, Elli Papaemmanuil, Scott C. Kogan, Klaus Schwarz, Mel Greaves, Markus Müschen, Rafael Casellas, David G. Schatz, Daniel Trageser, Soo-Mi Kweon, Nadine Henke, and Michael R. Lieber
- Subjects
Male ,Adolescent ,medicine.medical_treatment ,Immunoblotting ,Immunology ,Mice, Transgenic ,Mice, SCID ,Biology ,Somatic evolution in cancer ,Article ,Clonal Evolution ,Lesion ,Mice, Inbred NOD ,Cytidine Deaminase ,Precursor cell ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Immunology and Allergy ,Child ,Gene ,Childhood Acute Lymphoblastic Leukemia ,Homeodomain Proteins ,Mice, Knockout ,B-Lymphocytes ,Reverse Transcriptase Polymerase Chain Reaction ,Precursor Cells, B-Lymphoid ,Infant ,hemic and immune systems ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Flow Cytometry ,medicine.disease ,3. Good health ,DNA-Binding Proteins ,Leukemia ,Cytokine ,Microscopy, Fluorescence ,Child, Preschool ,Female ,medicine.symptom ,Clone (B-cell biology) ,Antibody Diversity - Abstract
© 2015 Nature America, Inc. All rights reserved. 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.
- Published
- 2015