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

Tim I. M. Malcolm, Patrick Villarese, Camilla J. Fairbairn, Laurence Lamant, Amélie Trinquand, C. Elizabeth Hook, G. A. Amos Burke, Laurence Brugières, Katherine Hughes, Dominique Payet, Olaf Merkel, Ana-Iris Schiefer, Ibraheem Ashankyty, Shahid Mian, Mariusz Wasik, Martin Turner, Lukas Kenner, Vahid Asnafi, Elizabeth Macintyre () and Suzanne D. Turner ()
Additional contact information
Tim I. M. Malcolm: University of Cambridge
Patrick Villarese: Hematology and INSERM1151, Institut Necker-Enfants Malades, Université Sorbonne Paris Cité at Descartes and Assistance Publique-Hôpitaux de Paris, Paris 75743, France
Camilla J. Fairbairn: University of Cambridge
Laurence Lamant: Institut Universitaire de Cancérologie Oncopole
Amélie Trinquand: Hematology and INSERM1151, Institut Necker-Enfants Malades, Université Sorbonne Paris Cité at Descartes and Assistance Publique-Hôpitaux de Paris, Paris 75743, France
C. Elizabeth Hook: Addenbrooke’s Hospital
G. A. Amos Burke: Addenbrooke’s Hospital
Laurence Brugières: Gustave Roussy
Katherine Hughes: University of Cambridge
Dominique Payet: Centre d’Immunologie de Marseille Luminy (CIML), INSERM UMR1104, CNRS UMR7280, Aix-Marseille Université UM2
Olaf Merkel: Clinical Institute of Pathology, Medical University of Vienna
Ana-Iris Schiefer: Clinical Institute of Pathology, Medical University of Vienna
Ibraheem Ashankyty: Molecular Diagnostics and Personalized Therapeutics Unit, College of Applied Medical Sciences University of Ha’il
Shahid Mian: Molecular Diagnostics and Personalized Therapeutics Unit, College of Applied Medical Sciences University of Ha’il
Mariusz Wasik: University of Pennsylvania
Martin Turner: The Babraham Institute
Lukas Kenner: Clinical Institute of Pathology, Medical University of Vienna
Vahid Asnafi: Hematology and INSERM1151, Institut Necker-Enfants Malades, Université Sorbonne Paris Cité at Descartes and Assistance Publique-Hôpitaux de Paris, Paris 75743, France
Elizabeth Macintyre: Hematology and INSERM1151, Institut Necker-Enfants Malades, Université Sorbonne Paris Cité at Descartes and Assistance Publique-Hôpitaux de Paris, Paris 75743, France
Suzanne D. Turner: University of Cambridge

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10087

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