title: Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia.
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.
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, CA, 94143.
authors.forename: Srividya
authors.initials: S
authors.lastname: Swaminathan
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, CA, 94143.|University of Freiburg, Faculty of Biology, 79104 Freiburg, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Klemm
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, CA, 94143.|Department of Haematology, University of Cambridge, Cambridge UK.
authors.forename: Eugene
authors.initials: E
authors.lastname: Park
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge UK.
authors.forename: Elli
authors.initials: E
authors.lastname: Papaemmanuil
authors.affiliation: Centre for Evolution and Cancer, The Institute of Cancer Research, London UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Ford
authors.affiliation: University of Southern California, Los Angeles, CA.
authors.forename: Soo-Mi
authors.initials: SM
authors.lastname: Kweon
authors.affiliation: University of Southern California, Los Angeles, CA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Trageser
authors.affiliation: University of Southern California, Los Angeles, CA.
authors.forename: Brian
authors.initials: B
authors.lastname: Hasselfeld
authors.affiliation: Heinrich-Heine-Universität Düsseldorf, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Henke
authors.affiliation: Heinrich-Heine-Universität Düsseldorf, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Mooster
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, CA, 94143.
authors.forename: Huimin
authors.initials: H
authors.lastname: Geng
authors.affiliation: Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, CA, 94143.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.affiliation: Genomics & Immunity, NIAMS, NIH, Bethesda, 20892, MD.
authors.forename: Rafael
authors.initials: R
authors.lastname: Casellas
authors.affiliation: Yale University, New Haven, CT.
authors.forename: David G
authors.initials: DG
authors.lastname: Schatz
authors.affiliation: University of Southern California, Los Angeles, CA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Lieber
authors.affiliation: Centre for Evolution and Cancer, The Institute of Cancer Research, London UK.
authors.forename: Mel F
authors.initials: MF
authors.lastname: Greaves
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, CA, 94143.|Department of Haematology, University of Cambridge, Cambridge UK.
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
mesh_terms: D000293:Adolescent; D000818:Animals; D000916:Antibody Diversity / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D060965:Clonal Evolution / Q000235:genetics / Q000276:immunology*; D003564:Cytidine Deaminase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007223:Infant; D008297:Male; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase