TY - JOUR
T1 - Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress
AU - Malcolm, Tim I.M.
AU - Villarese, Patrick
AU - Fairbairn, Camilla J.
AU - Lamant, Laurence
AU - Trinquand, Amélie
AU - Hook, C. Elizabeth
AU - Amos Burke, G. A.
AU - Brugières, Laurence
AU - Hughes, Katherine
AU - Payet, Dominique
AU - Merkel, Olaf
AU - Schiefer, Ana Iris
AU - Ashankyty, Ibraheem
AU - Mian, Shahid
AU - Wasik, Mariusz A.
AU - Turner, Martin
AU - Kenner, Lukas
AU - Asnafi, Vahid
AU - Macintyre, Elizabeth
AU - Turner, Suzanne D.
PY - 2016/1/12
Y1 - 2016/1/12
N2 - 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.
AB - 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.
KW - Adult
KW - Animals
KW - CD4 Antigens/metabolism
KW - Cell Line, Tumor
KW - Child
KW - Disease Models, Animal
KW - Female
KW - Flow Cytometry
KW - Gene Rearrangement, T-Lymphocyte
KW - Genes, RAG-1/genetics
KW - Genes, T-Cell Receptor alpha
KW - Genes, T-Cell Receptor beta
KW - Humans
KW - Immunohistochemistry
KW - Jurkat Cells
KW - Lymphoma, Large-Cell, Anaplastic/metabolism
KW - Male
KW - Mice
KW - Mice, Transgenic
KW - Protein-Tyrosine Kinases/metabolism
KW - Receptor, Notch1/metabolism
KW - Receptors, Antigen, T-Cell, alpha-beta/genetics
KW - Receptors, Antigen, T-Cell/metabolism
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Thymocytes/metabolism
KW - Thymus Gland/cytology
UR - http://www.scopus.com/inward/record.url?scp=84954510366&partnerID=8YFLogxK
U2 - 10.1038/ncomms10087
DO - 10.1038/ncomms10087
M3 - Article
C2 - 26753883
SN - 2041-1723
VL - 7
SP - 10087
JO - Nature Communications
JF - Nature Communications
M1 - 10087
ER -