title: Infection Exposure is a Causal Factor in B-cell Precursor Acute Lymphoblastic Leukemia as a Result of Pax5-Inherited Susceptibility.
abstract: Earlier in the past century, infections were regarded as the most likely cause of childhood B-cell precursor acute lymphoblastic leukemia (pB-ALL). However, there is a lack of relevant biologic evidence supporting this hypothesis. We present in vivo genetic evidence mechanistically connecting inherited susceptibility to pB-ALL and postnatal infections by showing that pB-ALL was initiated in Pax5 heterozygous mice only when they were exposed to common pathogens. Strikingly, these murine pB-ALLs closely resemble the human disease. Tumor exome sequencing revealed activating somatic, nonsynonymous mutations of Jak3 as a second hit. Transplantation experiments and deep sequencing suggest that inactivating mutations in Pax5 promote leukemogenesis by creating an aberrant progenitor compartment that is susceptible to malignant transformation through accumulation of secondary Jak3 mutations. Thus, treatment of Pax5(+/-) leukemic cells with specific JAK1/3 inhibitors resulted in increased apoptosis. These results uncover the causal role of infection in pB-ALL development.
  
  
  CONCLUSIONS
  These results demonstrate that delayed infection exposure is a causal factor in pB-ALL. Therefore, these findings have critical implications for the understanding of the pathogenesis of leukemia and for the development of novel therapies for this disease.
authors.affiliation: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Martín-Lorenzo
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Dusseldorf, Medical Faculty, Dusseldorf, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Hauer
authors.affiliation: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Vicente-Dueñas
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Dusseldorf, Medical Faculty, Dusseldorf, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Auer
authors.affiliation: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: González-Herrero
authors.affiliation: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.
authors.forename: Idoia
authors.initials: I
authors.lastname: García-Ramírez
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Dusseldorf, Medical Faculty, Dusseldorf, Germany. Department of Computer Science, Bonn-Rhein-Sieg University of Applied Sciences, Sankt Augustin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ginzel
authors.affiliation: Department of Computer Science, Bonn-Rhein-Sieg University of Applied Sciences, Sankt Augustin, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Thiele
authors.affiliation: Ludwig Institute for Cancer Research Brussels and Université catholique de Louvain, de Duve Institute, Brussels, Belgium.
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
authors.affiliation: Institute of Medical Informatics, University of Muenster, Muenster, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bartenhagen
authors.affiliation: Institute of Medical Informatics, University of Muenster, Muenster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Dugas
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Dusseldorf, Medical Faculty, Dusseldorf, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gombert
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Dusseldorf, Medical Faculty, Dusseldorf, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schäfer
authors.affiliation: Departamento de Anatomía Patológica, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Blanco
authors.affiliation: Servicio de Citometría and Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mayado
authors.affiliation: Servicio de Citometría and Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Orfao
authors.affiliation: Bioinformatics Unit, Cancer Research Center (CSIC-USAL), Salamanca, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Alonso-López
authors.affiliation: Bioinformatics Unit, Cancer Research Center (CSIC-USAL), Salamanca, Spain. Bioinformatics and Functional Genomics Research Group, Cancer Research Center (CSIC-USAL), Salamanca, Spain.
authors.forename: Javier De Las
authors.initials: Jde L
authors.lastname: Rivas
authors.affiliation: Centro de Biología Molecular Severo Ochoa; CSIC/Universidad Autónoma de Madrid; Campus de Cantoblanco, Madrid, Spain.
authors.forename: César
authors.initials: C
authors.lastname: Cobaleda
authors.affiliation: Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Maria Begoña
authors.initials: MB
authors.lastname: García-Cenador
authors.affiliation: Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: García-Criado
authors.affiliation: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain. Arndt.Borkhardt@med.uni-duesseldorf.de isg@usal.es.
authors.forename: Isidro
authors.initials: I
authors.lastname: Sánchez-García
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Dusseldorf, Medical Faculty, Dusseldorf, Germany. Arndt.Borkhardt@med.uni-duesseldorf.de isg@usal.es.
authors.forename: Arndt
authors.initials: A
authors.lastname: Borkhardt
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D059472:Exome; D005260:Female; D020869:Gene Expression Profiling; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D054884:Host-Pathogen Interactions; D015851:Interleukin-7 / Q000378:metabolism / Q000494:pharmacology; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D051757:PAX5 Transcription Factor / Q000235:genetics*; D010641:Phenotype; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology* / Q000473:pathology / Q000628:therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020395:Receptors, Interleukin-7 / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000235:genetics; D016662:Virus Integration
chemical_list: D015851:Interleukin-7; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D047428:Protein Kinase Inhibitors; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor; D053616:Janus Kinase 3