title: Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress.
abstract: Anaplastic large cell lymphoma (ALCL) is a peripheral T-cell lymphoma presenting mostly in children and young adults. The natural progression of this disease is largely unknown as is the identity of its true cell of origin. Here we present a model of peripheral ALCL pathogenesis where the malignancy is initiated in early thymocytes, before T-cell receptor (TCR) β-rearrangement, which is bypassed in CD4/NPM-ALK transgenic mice following Notch1 expression. However, we find that a TCR is required for thymic egress and development of peripheral murine tumours, yet this TCR must be downregulated for T-cell lymphomagenesis. In keeping with this, clonal TCR rearrangements in human ALCL are predominantly in-frame, but often aberrant, with clonal TCRα but no comparable clonal TCRβ rearrangement, yielding events that would not normally be permissive for survival during thymic development. Children affected by ALCL may thus harbour thymic lymphoma-initiating cells capable of seeding relapse after chemotherapy.
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge CB21QP, UK.
authors.forename: Tim I M
authors.initials: TI
authors.lastname: Malcolm
authors.affiliation: Hematology and INSERM1151, Institut Necker-Enfants Malades, Université Sorbonne Paris Cité at Descartes and Assistance Publique-Hôpitaux de Paris, Paris 75743, France.
authors.forename: Patrick
authors.identifier: http://orcid.org/0000-0003-1625-3785
authors.initials: P
authors.lastname: Villarese
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge CB21QP, UK.
authors.forename: Camilla J
authors.initials: CJ
authors.lastname: Fairbairn
authors.affiliation: Institut Universitaire de Cancérologie Oncopole, 1 Avenue Irène Joliot-Curie, Toulouse 31059, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Lamant
authors.affiliation: Hematology and INSERM1151, Institut Necker-Enfants Malades, Université Sorbonne Paris Cité at Descartes and Assistance Publique-Hôpitaux de Paris, Paris 75743, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Trinquand
authors.affiliation: Department of Histopathology and Cytology, Addenbrooke's Hospital, Cambridge CB20QQ, UK.
authors.forename: C Elizabeth
authors.initials: CE
authors.lastname: Hook
authors.affiliation: Department of Paediatric Oncology, Addenbrooke's Hospital, Cambridge CB20QQ, UK.
authors.forename: G A Amos
authors.initials: GA
authors.lastname: Burke
authors.affiliation: Département de Cancérologie de l'Enfant et l'Adolescent, Gustave Roussy, 114 rue Edouard Vaillant, Villejuif 94805, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Brugières
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge CB3OES, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: Hughes
authors.affiliation: Centre d'Immunologie de Marseille Luminy (CIML), INSERM UMR1104, CNRS UMR7280, Aix-Marseille Université UM2, Marseille 13288, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Payet
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna A-1090, Austria.
authors.forename: Olaf
authors.initials: O
authors.lastname: Merkel
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna A-1090, Austria.
authors.forename: Ana-Iris
authors.initials: AI
authors.lastname: Schiefer
authors.affiliation: Molecular Diagnostics and Personalized Therapeutics Unit, College of Applied Medical Sciences University of Ha'il, Ha'il, Kingdom of Saudi Arabia.
authors.forename: Ibraheem
authors.initials: I
authors.lastname: Ashankyty
authors.affiliation: Molecular Diagnostics and Personalized Therapeutics Unit, College of Applied Medical Sciences University of Ha'il, Ha'il, Kingdom of Saudi Arabia.
authors.forename: Shahid
authors.initials: S
authors.lastname: Mian
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6100, USA.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Wasik
authors.affiliation: The Babraham Institute, Cambridge CB223AT, UK.
authors.forename: Martin
authors.identifier: http://orcid.org/0000-0002-3801-9896
authors.initials: M
authors.lastname: Turner
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna A-1090, Austria.|Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Wahringerstrasse 13A, A-1090 Vienna, Austria.|Department of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
authors.affiliation: Hematology and INSERM1151, Institut Necker-Enfants Malades, Université Sorbonne Paris Cité at Descartes and Assistance Publique-Hôpitaux de Paris, Paris 75743, France.
authors.forename: Vahid
authors.initials: V
authors.lastname: Asnafi
authors.affiliation: Hematology and INSERM1151, Institut Necker-Enfants Malades, Université Sorbonne Paris Cité at Descartes and Assistance Publique-Hôpitaux de Paris, Paris 75743, France.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Macintyre
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge CB21QP, UK.
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Turner
mesh_terms: D000328:Adult; D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D045744:Cell Line, Tumor; D002648:Child; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D015329:Gene Rearrangement, T-Lymphocyte; D016654:Genes, RAG-1 / Q000235:genetics; D019673:Genes, T-Cell Receptor alpha; D019674:Genes, T-Cell Receptor beta; D006801:Humans; D007150:Immunohistochemistry; D019169:Jurkat Cells; D017728:Lymphoma, Large-Cell, Anaplastic / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D060168:Thymocytes / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology*
chemical_list: D015704:CD4 Antigens; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases