Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms10087
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Categories
Funding
- Bloodwise
- Leukaemia and Lymphoma Research
- bbsrc
- University of Ha'il, Kingdom of Saudi Arabia
- French Institut National de Cancer (INCa) PAIR Lymphoma T-COG [2008-021]
- RT-07 Immature T/My leukemia 'Recherche Translationnelle' programmes
- INCa PAIR Lymphoma T-COG
- Cambridge NIHR BRC Cell Phenotyping Hub
- Enfants et Sante and Societe Francaise de Cancers de l'Enfant (SFCE)
- Association Laurette Fugain [ALF2012-09]
- BBSRC [BBS/E/B/0000H190, BBS/E/B/000C0409, BBS/E/B/000C0407] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/E/B/0000H190, BBS/E/B/000C0407, 1431508, BBS/E/B/000C0409] Funding Source: researchfish
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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) beta-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 TCR alpha but no comparable clonal TCR beta 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.
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