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Nat Commun. 2016 Jan 12;7:10087. doi: 10.1038/ncomms10087.

Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress.

Author information

1
Department of Pathology, University of Cambridge, Cambridge CB21QP, UK.
2
Hematology and INSERM1151, Institut Necker-Enfants Malades, Université Sorbonne Paris Cité at Descartes and Assistance Publique-Hôpitaux de Paris, Paris 75743, France.
3
Institut Universitaire de Cancérologie Oncopole, 1 Avenue Irène Joliot-Curie, Toulouse 31059, France.
4
Department of Histopathology and Cytology, Addenbrooke's Hospital, Cambridge CB20QQ, UK.
5
Department of Paediatric Oncology, Addenbrooke's Hospital, Cambridge CB20QQ, UK.
6
Département de Cancérologie de l'Enfant et l'Adolescent, Gustave Roussy, 114 rue Edouard Vaillant, Villejuif 94805, France.
7
Department of Veterinary Medicine, University of Cambridge, Cambridge CB3OES, UK.
8
Centre d'Immunologie de Marseille Luminy (CIML), INSERM UMR1104, CNRS UMR7280, Aix-Marseille Université UM2, Marseille 13288, France.
9
Clinical Institute of Pathology, Medical University of Vienna, Vienna A-1090, Austria.
10
Molecular Diagnostics and Personalized Therapeutics Unit, College of Applied Medical Sciences University of Ha'il, Ha'il, Kingdom of Saudi Arabia.
11
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6100, USA.
12
The Babraham Institute, Cambridge CB223AT, UK.
13
Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Wahringerstrasse 13A, A-1090 Vienna, Austria.
14
Department of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.

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.

PMID:
26753883
PMCID:
PMC4729925
DOI:
10.1038/ncomms10087
[Indexed for MEDLINE]
Free PMC Article

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