GAPDH Overexpression in the T Cell Lineage Promotes Angioimmunoblastic T Cell Lymphoma through an NF-κB-Dependent Mechanism

Laura Mondragón; Rana Mhaidly; Gian Marco De Donatis; Marie Tosolini; Pascal Dao; Anthony R. Martin; Caroline Pons; Johanna Chiche; Marie Jacquin; Véronique Imbert; Emma Proïcs; Laurent Boyer; Anne Doye; Frédéric Luciano; Jaap G. Neels; Frédéric Coutant; Nicole Fabien; Laura Sormani; Camila Rubio-Patiño; Jozef P. Bossowski; Florian Muller; Sandrine Marchetti; Elodie Villa; Jean François Peyron; Philippe Gaulard; François Lemonnier; Vahid Asnafi; Laurent Genestier; Rachid Benhida; Jean Jacques Fournié; Thierry Passeron; Jean Ehrland Ricci; Els Verhoeyen

doi:10.1016/j.ccell.2019.07.008

GAPDH Overexpression in the T Cell Lineage Promotes Angioimmunoblastic T Cell Lymphoma through an NF-κB-Dependent Mechanism

Laura Mondragón, Rana Mhaidly, Gian Marco De Donatis, Marie Tosolini, Pascal Dao, Anthony R. Martin, Caroline Pons, Johanna Chiche, Marie Jacquin, Véronique Imbert, Emma Proïcs, Laurent Boyer, Anne Doye, Frédéric Luciano, Jaap G. Neels, Frédéric Coutant, Nicole Fabien, Laura Sormani, Camila Rubio-Patiño, Jozef P. BossowskiFlorian Muller, Sandrine Marchetti, Elodie Villa, Jean François Peyron, Philippe Gaulard, François Lemonnier, Vahid Asnafi, Laurent Genestier, Rachid Benhida, Jean Jacques Fournié, Thierry Passeron, Jean Ehrland Ricci, Els Verhoeyen

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44 Scopus citations

Abstract

GAPDH is emerging as a key player in T cell development and function. To investigate the role of GAPDH in T cells, we generated a transgenic mouse model overexpressing GAPDH in the T cell lineage. Aged mice developed a peripheral Tfh-like lymphoma that recapitulated key molecular, pathological, and immunophenotypic features of human angioimmunoblastic T cell lymphoma (AITL). GAPDH induced non-canonical NF-κB pathway activation in mouse T cells, which was strongly activated in human AITL. We developed a NIK inhibitor to reveal that targeting the NF-κB pathway prolonged AITL-bearing mouse survival alone and in combination with anti-PD-1. These findings suggest the therapeutic potential of targeting NF-κB signaling in AITL and provide a model for future AITL therapeutic investigations.

Original language	English
Pages (from-to)	268-287.e10
Journal	Cancer Cell
Volume	36
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2019.07.008
State	Published - 16 Sep 2019
Externally published	Yes

Keywords

NF-κB pathway
NF-κB-inducing kinase
PD1
T follicular helper cells
angioimmunoblastic T cell lymphoma
anti-PD1 immunotherapy
germinal center B cells
glyceraldehyde-3-phosphate-dehydrogenase
glycolytic enzyme
preclinical mouse model for AITL

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10.1016/j.ccell.2019.07.008

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Mondragón, L., Mhaidly, R., De Donatis, G. M., Tosolini, M., Dao, P., Martin, A. R., Pons, C., Chiche, J., Jacquin, M., Imbert, V., Proïcs, E., Boyer, L., Doye, A., Luciano, F., Neels, J. G., Coutant, F., Fabien, N., Sormani, L., Rubio-Patiño, C., ... Verhoeyen, E. (2019). GAPDH Overexpression in the T Cell Lineage Promotes Angioimmunoblastic T Cell Lymphoma through an NF-κB-Dependent Mechanism. Cancer Cell, 36(3), 268-287.e10. https://doi.org/10.1016/j.ccell.2019.07.008

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title = "GAPDH Overexpression in the T Cell Lineage Promotes Angioimmunoblastic T Cell Lymphoma through an NF-κB-Dependent Mechanism",

abstract = "GAPDH is emerging as a key player in T cell development and function. To investigate the role of GAPDH in T cells, we generated a transgenic mouse model overexpressing GAPDH in the T cell lineage. Aged mice developed a peripheral Tfh-like lymphoma that recapitulated key molecular, pathological, and immunophenotypic features of human angioimmunoblastic T cell lymphoma (AITL). GAPDH induced non-canonical NF-κB pathway activation in mouse T cells, which was strongly activated in human AITL. We developed a NIK inhibitor to reveal that targeting the NF-κB pathway prolonged AITL-bearing mouse survival alone and in combination with anti-PD-1. These findings suggest the therapeutic potential of targeting NF-κB signaling in AITL and provide a model for future AITL therapeutic investigations.",

keywords = "NF-κB pathway, NF-κB-inducing kinase, PD1, T follicular helper cells, angioimmunoblastic T cell lymphoma, anti-PD1 immunotherapy, germinal center B cells, glyceraldehyde-3-phosphate-dehydrogenase, glycolytic enzyme, preclinical mouse model for AITL",

author = "Laura Mondrag{\'o}n and Rana Mhaidly and {De Donatis}, {Gian Marco} and Marie Tosolini and Pascal Dao and Martin, {Anthony R.} and Caroline Pons and Johanna Chiche and Marie Jacquin and V{\'e}ronique Imbert and Emma Pro{\"i}cs and Laurent Boyer and Anne Doye and Fr{\'e}d{\'e}ric Luciano and Neels, {Jaap G.} and Fr{\'e}d{\'e}ric Coutant and Nicole Fabien and Laura Sormani and Camila Rubio-Pati{\~n}o and Bossowski, {Jozef P.} and Florian Muller and Sandrine Marchetti and Elodie Villa and Peyron, {Jean Fran{\c c}ois} and Philippe Gaulard and Fran{\c c}ois Lemonnier and Vahid Asnafi and Laurent Genestier and Rachid Benhida and Fourni{\'e}, {Jean Jacques} and Thierry Passeron and Ricci, {Jean Ehrland} and Els Verhoeyen",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = sep,

day = "16",

doi = "10.1016/j.ccell.2019.07.008",

language = "English",

volume = "36",

pages = "268--287.e10",

journal = "Cancer Cell",

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Mondragón, L, Mhaidly, R, De Donatis, GM, Tosolini, M, Dao, P, Martin, AR, Pons, C, Chiche, J, Jacquin, M, Imbert, V, Proïcs, E, Boyer, L, Doye, A, Luciano, F, Neels, JG, Coutant, F, Fabien, N, Sormani, L, Rubio-Patiño, C, Bossowski, JP, Muller, F, Marchetti, S, Villa, E, Peyron, JF, Gaulard, P, Lemonnier, F, Asnafi, V, Genestier, L, Benhida, R, Fournié, JJ, Passeron, T, Ricci, JE & Verhoeyen, E 2019, 'GAPDH Overexpression in the T Cell Lineage Promotes Angioimmunoblastic T Cell Lymphoma through an NF-κB-Dependent Mechanism', Cancer Cell, vol. 36, no. 3, pp. 268-287.e10. https://doi.org/10.1016/j.ccell.2019.07.008

TY - JOUR

T1 - GAPDH Overexpression in the T Cell Lineage Promotes Angioimmunoblastic T Cell Lymphoma through an NF-κB-Dependent Mechanism

AU - Mondragón, Laura

AU - Mhaidly, Rana

AU - De Donatis, Gian Marco

AU - Tosolini, Marie

AU - Dao, Pascal

AU - Martin, Anthony R.

AU - Pons, Caroline

AU - Chiche, Johanna

AU - Jacquin, Marie

AU - Imbert, Véronique

AU - Proïcs, Emma

AU - Boyer, Laurent

AU - Doye, Anne

AU - Luciano, Frédéric

AU - Neels, Jaap G.

AU - Coutant, Frédéric

AU - Fabien, Nicole

AU - Sormani, Laura

AU - Rubio-Patiño, Camila

AU - Bossowski, Jozef P.

AU - Muller, Florian

AU - Marchetti, Sandrine

AU - Villa, Elodie

AU - Peyron, Jean François

AU - Gaulard, Philippe

AU - Lemonnier, François

AU - Asnafi, Vahid

AU - Genestier, Laurent

AU - Benhida, Rachid

AU - Fournié, Jean Jacques

AU - Passeron, Thierry

AU - Ricci, Jean Ehrland

AU - Verhoeyen, Els

PY - 2019/9/16

Y1 - 2019/9/16

N2 - GAPDH is emerging as a key player in T cell development and function. To investigate the role of GAPDH in T cells, we generated a transgenic mouse model overexpressing GAPDH in the T cell lineage. Aged mice developed a peripheral Tfh-like lymphoma that recapitulated key molecular, pathological, and immunophenotypic features of human angioimmunoblastic T cell lymphoma (AITL). GAPDH induced non-canonical NF-κB pathway activation in mouse T cells, which was strongly activated in human AITL. We developed a NIK inhibitor to reveal that targeting the NF-κB pathway prolonged AITL-bearing mouse survival alone and in combination with anti-PD-1. These findings suggest the therapeutic potential of targeting NF-κB signaling in AITL and provide a model for future AITL therapeutic investigations.

AB - GAPDH is emerging as a key player in T cell development and function. To investigate the role of GAPDH in T cells, we generated a transgenic mouse model overexpressing GAPDH in the T cell lineage. Aged mice developed a peripheral Tfh-like lymphoma that recapitulated key molecular, pathological, and immunophenotypic features of human angioimmunoblastic T cell lymphoma (AITL). GAPDH induced non-canonical NF-κB pathway activation in mouse T cells, which was strongly activated in human AITL. We developed a NIK inhibitor to reveal that targeting the NF-κB pathway prolonged AITL-bearing mouse survival alone and in combination with anti-PD-1. These findings suggest the therapeutic potential of targeting NF-κB signaling in AITL and provide a model for future AITL therapeutic investigations.

KW - NF-κB pathway

KW - NF-κB-inducing kinase

KW - PD1

KW - T follicular helper cells

KW - angioimmunoblastic T cell lymphoma

KW - anti-PD1 immunotherapy

KW - germinal center B cells

KW - glyceraldehyde-3-phosphate-dehydrogenase

KW - glycolytic enzyme

KW - preclinical mouse model for AITL

UR - http://www.scopus.com/inward/record.url?scp=85071907172&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2019.07.008

DO - 10.1016/j.ccell.2019.07.008

M3 - Article

C2 - 31447347

AN - SCOPUS:85071907172

SN - 1535-6108

VL - 36

SP - 268-287.e10

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -

GAPDH Overexpression in the T Cell Lineage Promotes Angioimmunoblastic T Cell Lymphoma through an NF-κB-Dependent Mechanism

Abstract

Keywords

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