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; Suzanne D. Turner

doi:10.1038/ncomms10087

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^*, Suzanne D. Turner

^*Corresponding author for this work

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	10087
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10087
Publication status	Published - 12 Jan 2016

Bibliographical note

Funding Information:
S.D.T., L.K., O.M., L.B. and L.L. are members of the European Research Initiative for ALK-Related Malignancies (www.erialcl.net). S.D.T. receives funding from Bloodwise. T.I.M. was in receipt of a Gordon Piller PhD studentship from Leukaemia and Lymphoma Research at the time of the study. C.J.F. is supported with PhD funding from the bbsrc. S.D.T., S.M., I.A. and T.I.M. 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 (No 2008-021) and RT-07 Immature T/My leukemia ''Recherche Translationnelle'' programmes and MD/PhD grant funding to A.T., 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. We are grateful to Dr Phil G. Stevenson, Department of Pathology, University of Cambridge, UK for providing MHV68 for our studies, Professor Jean Soulier for CGH array analysis of human ALCL samples, Michaela Schlederer for her excellent technical assistance and Mohamed Belhocine for bioinformatics assistance.

Funding Information:
S.D.T., L.K., O.M., L.B. and L.L. are members of the European Research Initiative for ALK-Related Malignancies (www.erialcl.net). S.D.T. receives funding from Bloodwise. T.I.M. was in receipt of a Gordon Piller PhD studentship from Leukaemia and Lymphoma Research at the time of the study. C.J.F. is supported with PhD funding from the bbsrc. S.D.T., S.M., I.A. and T.I.M. 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.T., the Enfants et Santé and Société Franc¸aise 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. We are grateful to Dr Phil G. Stevenson, Department of Pathology, University of Cambridge, UK for providing MHV68 for our studies, Professor Jean Soulier for CGH array analysis of human ALCL samples, Michaela Schlederer for her excellent technical assistance and Mohamed Bel-hocine for bioinformatics assistance.

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/ncomms10087

Cite this

Malcolm, T. I. M., Villarese, P., Fairbairn, C. J., Lamant, L., Trinquand, A., Hook, C. E., Burke, G. A. A., Brugières, L., Hughes, K., Payet, D., Merkel, O., Schiefer, A. I., Ashankyty, I., Mian, S., Wasik, M., Turner, M., Kenner, L., Asnafi, V., Macintyre, E., & Turner, S. D. (2016). Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress. Nature Communications, 7, Article 10087. https://doi.org/10.1038/ncomms10087

@article{a1b606ab3a3d45688bd2da92adc42ce9,

title = "Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress",

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.",

author = "Malcolm, {Tim I.M.} and Patrick Villarese and Fairbairn, {Camilla J.} and Laurence Lamant and Am{\'e}lie Trinquand and Hook, {C. Elizabeth} and Burke, {G. A.Amos} and Laurence Brugi{\`e}res and Katherine Hughes and Dominique Payet and Olaf Merkel and Schiefer, {Ana Iris} and Ibraheem Ashankyty and Shahid Mian and Mariusz Wasik and Martin Turner and Lukas Kenner and Vahid Asnafi and Elizabeth Macintyre and Turner, {Suzanne D.}",

note = "Funding Information: S.D.T., L.K., O.M., L.B. and L.L. are members of the European Research Initiative for ALK-Related Malignancies (www.erialcl.net). S.D.T. receives funding from Bloodwise. T.I.M. was in receipt of a Gordon Piller PhD studentship from Leukaemia and Lymphoma Research at the time of the study. C.J.F. is supported with PhD funding from the bbsrc. S.D.T., S.M., I.A. and T.I.M. 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 (No 2008-021) and RT-07 Immature T/My leukemia ''Recherche Translationnelle'' programmes and MD/PhD grant funding to A.T., the Enfants et Sant{\'e} and Soci{\'e}t{\'e} Fran{\c c}aise 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. We are grateful to Dr Phil G. Stevenson, Department of Pathology, University of Cambridge, UK for providing MHV68 for our studies, Professor Jean Soulier for CGH array analysis of human ALCL samples, Michaela Schlederer for her excellent technical assistance and Mohamed Belhocine for bioinformatics assistance. Funding Information: S.D.T., L.K., O.M., L.B. and L.L. are members of the European Research Initiative for ALK-Related Malignancies (www.erialcl.net). S.D.T. receives funding from Bloodwise. T.I.M. was in receipt of a Gordon Piller PhD studentship from Leukaemia and Lymphoma Research at the time of the study. C.J.F. is supported with PhD funding from the bbsrc. S.D.T., S.M., I.A. and T.I.M. are supported with funding from the University of Ha{\textquoteright}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 {\textquoteleft}Recherche Translationnelle{\textquoteright} programmes and MD/ PhD grant funding to A.T., the Enfants et Sant{\'e} and Soci{\'e}t{\'e} Franc¸aise de Cancers de l{\textquoteright}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. We are grateful to Dr Phil G. Stevenson, Department of Pathology, University of Cambridge, UK for providing MHV68 for our studies, Professor Jean Soulier for CGH array analysis of human ALCL samples, Michaela Schlederer for her excellent technical assistance and Mohamed Bel-hocine for bioinformatics assistance.",

year = "2016",

month = jan,

day = "12",

doi = "10.1038/ncomms10087",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Springer",

}

Malcolm, TIM, Villarese, P, Fairbairn, CJ, Lamant, L, Trinquand, A, Hook, CE, Burke, GAA, Brugières, L, Hughes, K, Payet, D, Merkel, O, Schiefer, AI, Ashankyty, I, Mian, S, Wasik, M, Turner, M, Kenner, L, Asnafi, V, Macintyre, E & Turner, SD 2016, 'Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress', Nature Communications, vol. 7, 10087. https://doi.org/10.1038/ncomms10087

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 - Burke, G. A.Amos

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

AU - Turner, Martin

AU - Kenner, Lukas

AU - Asnafi, Vahid

AU - Macintyre, Elizabeth

AU - Turner, Suzanne D.

N1 - Funding Information: S.D.T., L.K., O.M., L.B. and L.L. are members of the European Research Initiative for ALK-Related Malignancies (www.erialcl.net). S.D.T. receives funding from Bloodwise. T.I.M. was in receipt of a Gordon Piller PhD studentship from Leukaemia and Lymphoma Research at the time of the study. C.J.F. is supported with PhD funding from the bbsrc. S.D.T., S.M., I.A. and T.I.M. 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 (No 2008-021) and RT-07 Immature T/My leukemia ''Recherche Translationnelle'' programmes and MD/PhD grant funding to A.T., 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. We are grateful to Dr Phil G. Stevenson, Department of Pathology, University of Cambridge, UK for providing MHV68 for our studies, Professor Jean Soulier for CGH array analysis of human ALCL samples, Michaela Schlederer for her excellent technical assistance and Mohamed Belhocine for bioinformatics assistance. Funding Information: S.D.T., L.K., O.M., L.B. and L.L. are members of the European Research Initiative for ALK-Related Malignancies (www.erialcl.net). S.D.T. receives funding from Bloodwise. T.I.M. was in receipt of a Gordon Piller PhD studentship from Leukaemia and Lymphoma Research at the time of the study. C.J.F. is supported with PhD funding from the bbsrc. S.D.T., S.M., I.A. and T.I.M. 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.T., the Enfants et Santé and Société Franc¸aise 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. We are grateful to Dr Phil G. Stevenson, Department of Pathology, University of Cambridge, UK for providing MHV68 for our studies, Professor Jean Soulier for CGH array analysis of human ALCL samples, Michaela Schlederer for her excellent technical assistance and Mohamed Bel-hocine for bioinformatics assistance.

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.

UR - http://www.scopus.com/inward/record.url?scp=84954510366&partnerID=8YFLogxK

U2 - 10.1038/ncomms10087

DO - 10.1038/ncomms10087

M3 - Article

C2 - 26753883

AN - SCOPUS:84954510366

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 10087

ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

Access to Document

Fingerprint

Cite this