Anaplastic large cell lymphoma arises in thymocytes and requires transient T cell receptor expression for thymic egress
Hook, Catherine Elizabeth
Burke, GA Amos
Thymic origin of ALCL
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Malcolm, T., Villarese, P., Fairbairn, C., Lamant, L., Trinquand, A., Hook, C. E., Burke, G. A., et al. (2015). Anaplastic large cell lymphoma arises in thymocytes and requires transient T cell receptor expression for thymic egress. Nature Communications, 7 (10087)https://doi.org/10.1038/ncomms10087
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 in which the malignancy is initiated in early thymocytes, prior to 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 tumors, yet this TCR must be down‐regulated 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 harbor thymic lymphoma‐initiating cells capable of seeding relapse after chemotherapy.
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.
Leukaemia & Lymphoma Research (12065)
Leukaemia & Lymphoma Research (8064)
External DOI: https://doi.org/10.1038/ncomms10087
This record's URL: https://www.repository.cam.ac.uk/handle/1810/252451
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