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


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Type

Article

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Authors

Malcolm, Tim IM 
Fairbairn, Camilla J 
Lamant, Laurence 
Trinquand, Amélie 

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.

Description

Keywords

Adult, Animals, CD4 Antigens, Cell Line, Tumor, Child, Disease Models, Animal, Female, Flow Cytometry, Gene Rearrangement, T-Lymphocyte, Genes, RAG-1, Genes, T-Cell Receptor alpha, Genes, T-Cell Receptor beta, Humans, Immunohistochemistry, Jurkat Cells, Lymphoma, Large-Cell, Anaplastic, Male, Mice, Mice, Transgenic, Protein-Tyrosine Kinases, Receptor, Notch1, Receptors, Antigen, T-Cell, Receptors, Antigen, T-Cell, alpha-beta, Reverse Transcriptase Polymerase Chain Reaction, Thymocytes, Thymus Gland

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

7

Publisher

Springer Science and Business Media LLC
Sponsorship
Leukaemia & Lymphoma Research (12065)
Leukaemia & Lymphoma Research (8064)
SDT receives funding from Bloodwise. TM was in receipt of a Gordon Piller PhD studentship from Leukaemia and Lymphoma Research at the time of the study. CF is supported with PhD funding from the bbsrc. SDT, SM, IA and TM are supported with funding from the University of Ha’il, Kingdom of Saudi Arabia. Support to the Macintyre laboratory includes the French Institut National de Cancer (INCa) PAIR Lymphoma T-COG (N° 2008-021) and RT-07 Immature T/My leukemia “Recherche Translationnelle” programmes and MD/PhD grant funding to A Trinquand, the Enfants et Santé and Société Française de Cancers de l’Enfant (SFCE) and the Association Laurette Fugain (ALF2012-09). Support to the Lamant laboratory includes INCa PAIR Lymphoma T-COG. This research was supported by the Cambridge NIHR BRC Cell Phenotyping Hub.