title: Two types of BCR interactions are positively selected during leukemia development in the Eμ-TCL1 transgenic mouse model of CLL.
abstract: Chronic lymphocytic leukemia (CLL) is a common B-cell malignancy characterized by a highly variable course and outcome. The disease is believed to be driven by B-cell receptor (BCR) signals generated by external antigens and/or cell-autonomous BCR interactions, but direct in vivo evidence for this is still lacking. To further define the role of the BCR pathway in the development and progression of CLL, we evaluated the capacity of different types of antigen/BCR interactions to induce leukemia in the Eμ-TCL1 transgenic mouse model. We show that cell autonomous signaling capacity is a uniform characteristic of the leukemia-derived BCRs and represents a prerequisite for CLL development. Low-affinity BCR interactions with autoantigens generated during apoptosis are also positively selected, suggesting that they contribute to the pathogenesis of the disease. In contrast, high-affinity BCR interactions are not selected, regardless of antigen form or presentation. We also show that the capacity of the leukemic cells to respond to cognate antigen correlates inversely with time to leukemia development, suggesting that signals induced by external antigen increase the aggressiveness of the disease. Collectively, these findings provide in vivo evidence that the BCR pathway drives the development and can influence the clinical course of CLL.
authors.affiliation: Molecular Hematology, International Centre for Genetic Engineering and Biotechnology, Rome, Italy;
authors.forename: Stefano
authors.initials: S
authors.lastname: Iacovelli
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany;
authors.forename: Eva
authors.initials: E
authors.lastname: Hug
authors.affiliation: Molecular Hematology, International Centre for Genetic Engineering and Biotechnology, Rome, Italy;
authors.forename: Sara
authors.initials: S
authors.lastname: Bennardo
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany;
authors.forename: Marcus
authors.initials: M
authors.lastname: Duehren-von Minden
authors.affiliation: Molecular Hematology, International Centre for Genetic Engineering and Biotechnology, Rome, Italy;
authors.forename: Stefania
authors.initials: S
authors.lastname: Gobessi
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland;
authors.forename: Andrea
authors.initials: A
authors.lastname: Rinaldi
authors.affiliation: Molecular Hematology, International Centre for Genetic Engineering and Biotechnology, Rome, Italy;
authors.forename: Mirza
authors.initials: M
authors.lastname: Suljagic
authors.affiliation: European Molecular Biology Laboratory, Rome, Italy;
authors.forename: Daniel
authors.initials: D
authors.lastname: Bilbao
authors.affiliation: European Molecular Biology Laboratory, Rome, Italy;
authors.forename: Giulia
authors.initials: G
authors.lastname: Bolasco
authors.affiliation: Department of Otorhinolaryngology, Medical University of Vienna, Vienna, Austria;
authors.forename: Julia
authors.initials: J
authors.lastname: Eckl-Dorna
authors.affiliation: Department of Otorhinolaryngology, Medical University of Vienna, Vienna, Austria;
authors.forename: Verena
authors.initials: V
authors.lastname: Niederberger
authors.affiliation: Department of Hematology, Catholic University Hospital "A. Gemelli," Rome, Italy;
authors.forename: Francesco
authors.initials: F
authors.lastname: Autore
authors.affiliation: Department of Hematology, Catholic University Hospital "A. Gemelli," Rome, Italy;
authors.forename: Simona
authors.initials: S
authors.lastname: Sica
authors.affiliation: Department of Hematology, Catholic University Hospital "A. Gemelli," Rome, Italy;
authors.forename: Luca
authors.initials: L
authors.lastname: Laurenti
authors.affiliation: Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD;
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Wang
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom;
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cornall
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC;
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Clarke
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH;
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland; IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; and.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertoni
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany; Institute of Immunology, University Clinics Ulm, Ulm, Germany.
authors.forename: Hassan
authors.initials: H
authors.lastname: Jumaa
authors.affiliation: Molecular Hematology, International Centre for Genetic Engineering and Biotechnology, Rome, Italy;
authors.forename: Dimitar G
authors.initials: DG
authors.lastname: Efremov
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D001324:Autoantigens / Q000235:genetics; D018450:Disease Progression; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D006801:Humans; D007942:Leukemia, Experimental / Q000209:etiology / Q000235:genetics / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000209:etiology* / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009113:Muramidase / Q000235:genetics / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D055517:snRNP Core Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D001324:Autoantigens; D011518:Proto-Oncogene Proteins; D011947:Receptors, Antigen, B-Cell; C090851:TCL1A protein, human; D055517:snRNP Core Proteins; D009113:Muramidase