title: The RAG-1/2 endonuclease causes genomic instability and controls CNS complications of lymphoblastic leukemia in p53/Prkdc-deficient mice.
abstract: Double-strand DNA breaks (DSB) induce chromosomal translocations and gene amplification in cell culture, but mechanisms by which DSB cause genomic instability in vivo are poorly understood. We show that RAG-1/2-induced DSB cause IgH/c-Myc translocations in leukemic pro-B cells from p53/Prkdc-deficient mice. Strikingly, these translocations were complex, clonally heterogeneous and amplified. We observed reiterated IgH/c-Myc fusions on dicentric chromosomes, suggesting that amplification occurred by repeated cycles of bridge, breakage and fusion. Leukemogenesis was not mitigated in RAG-2/p53/Prkdc-deficient mice, but leukemic pro-B cells lacked IgH/c-Myc translocations. Thus, global genomic instability conferred by p53/Prkdc disruption efficiently transforms pro-B cells lacking RAG-1/2-induced DSB. Unexpectedly, RAG-2/p53/Prkdc-deficient mice also developed leptomeningeal leukemia, providing a novel spontaneous model for this frequent complication of human lymphoblastic malignancies.
authors.affiliation: Program in Developmental Biology, The Hospital for Sick Children and Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Gladdy
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Williams
authors.forename: Ildiko
authors.initials: I
authors.lastname: Grandal
authors.forename: Jana
authors.initials: J
authors.lastname: Karaskova
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Squire
authors.forename: James T
authors.initials: JT
authors.lastname: Rutka
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Guidos
authors.forename: Jayne S
authors.initials: JS
authors.lastname: Danska
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015139:Blotting, Southern; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002493:Central Nervous System Diseases / Q000209:etiology / Q000473:pathology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D005434:Flow Cytometry; D005784:Gene Amplification / Q000235:genetics; D016259:Genes, myc / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007945:Leukemia, Lymphoid / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D008577:Meningeal Neoplasms / Q000209:etiology / Q000235:genetics; D051379:Mice; D023421:Models, Animal; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007143:Immunoglobulin Heavy Chains; C499308:Rag2 protein, mouse; D016159:Tumor Suppressor Protein p53; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein