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

Research output: Contribution to journalArticlepeer-review

31 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 languageEnglish
Pages (from-to)268-287.e10
JournalCancer Cell
Volume36
Issue number3
DOIs
StatePublished - 16 Sep 2019
Externally publishedYes

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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