title: MuLV-related endogenous retroviral elements and Flt3 participate in aberrant end-joining events that promote B-cell leukemogenesis.
abstract: During V(D)J recombination of immunoglobulin genes, p53 and nonhomologous end-joining (NHEJ) suppress aberrant rejoining of DNA double-strand breaks induced by recombinase-activating genes (Rags)-1/2, thus maintaining genomic stability and limiting malignant transformation during B-cell development. However, Rag deficiency does not prevent B-cell leukemogenesis in p53/NHEJ mutant mice, revealing that p53 and NHEJ also suppress Rag-independent mechanisms of B-cell leukemogenesis. Using several cytogenomic approaches, we identified a novel class of activating mutations in Fms-like tyrosine kinase 3 (Flt3), a receptor tyrosine kinase important for normal hematopoiesis in Rag/p53/NHEJ triple-mutant (TM) B-cell leukemias. These mutant Flt3 alleles were created by complex genomic rearrangements with Moloney leukemia virus (MuLV)-related endogenous retroviral (ERV) elements, generating ERV-Flt3 fusion genes encoding an N-terminally truncated mutant form of Flt3 (trFlt3) that was transcribed from ERV long terminal repeats. trFlt3 protein lacked most of the Flt3 extracellular domain and induced ligand-independent STAT5 phosphorylation and proliferation of hematopoietic progenitor cells. Furthermore, expression of trFlt3 in p53/NHEJ mutant hematopoietic progenitor cells promoted development of clinically aggressive B-cell leukemia. Thus, repetitive MuLV-related ERV sequences can participate in aberrant end-joining events that promote development of aggressive B-cell leukemia.
authors.affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada; Department of Immunology.
authors.forename: Radia M
authors.initials: RM
authors.lastname: Johnson
authors.affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
authors.forename: Eniko
authors.initials: E
authors.lastname: Papp
authors.affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada;
authors.forename: Ildiko
authors.initials: I
authors.lastname: Grandal
authors.affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada;
authors.forename: Paul E
authors.initials: PE
authors.lastname: Kowalski
authors.affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada;
authors.forename: Lauryl
authors.initials: L
authors.lastname: Nutter
authors.affiliation: The Centre for Applied Genomics, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada;
authors.forename: Raymond C C
authors.initials: RC
authors.lastname: Wong
authors.affiliation: The Centre for Applied Genomics, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada; Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Joseph-George
authors.affiliation: Department of Immunology, Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada.
authors.forename: Jayne S
authors.initials: JS
authors.lastname: Danska
authors.affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada; Department of Immunology.
authors.forename: Cynthia J
authors.identifier: http://orcid.org/0000-0002-7674-2612
authors.initials: CJ
authors.lastname: Guidos
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000473:pathology; D049109:Cell Proliferation; D059766:DNA End-Joining Repair / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000166:cytology; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008979:Moloney murine leukemia virus / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011995:Recombination, Genetic; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D050799:STAT5 Transcription Factor; D051941:fms-Like Tyrosine Kinase 3
keywords: B-cell development; Fms-like tyrosine kinase 3; endogenous retrovirus; lymphoblastic leukemia; nonhomologous end-joining; p53