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

  • Cancer Cell. 2019 Sep 16;36(3):268-287.e10. doi: 10.1016/j.ccell.2019.07.008.
Laura Mondragón  1 ,  Rana Mhaidly  1 ,  Gian Marco De Donatis  1 ,  Marie Tosolini  2 ,  Pascal Dao  3 ,  Anthony R Martin  3 ,  Caroline Pons  1 ,  Johanna Chiche  1 ,  Marie Jacquin  1 ,  Véronique Imbert  1 ,  Emma Proïcs  1 ,  Laurent Boyer  1 ,  Anne Doye  1 ,  Frédéric Luciano  1 ,  Jaap G Neels  1 ,  Frédéric Coutant  4 ,  Nicole Fabien  5 ,  Laura Sormani  1 ,  Camila Rubio-Patiño  1 ,  Jozef P Bossowski  1 ,  Florian Muller  1 ,  Sandrine Marchetti  1 ,  Elodie Villa  1 ,  Jean-François Peyron  1 ,  Philippe Gaulard  6 ,  François Lemonnier  7 ,  Vahid Asnafi  8 ,  Laurent Genestier  9 ,  Rachid Benhida  3 ,  Jean-Jacques Fournié  10 ,  Thierry Passeron  11 ,  Jean-Ehrland Ricci  12 ,  Els Verhoeyen  13
Affiliations
  • 1. Université Côte d'Azur, INSERM, C3M, 06204 Nice, France.
  • 2. Pôle Technologique du CRCT - Plateau Bioinformatique INSERM-UMR 1037, Toulouse, France.
  • 3. Institut de Chimie de Nice UMR UNS-CNRS 7272, Université Nice Sophia Antipolis, Parc Valrose, 06108 Nice, France.
  • 4. Immunology Department, Lyon-Sud Hospital, Hospices Civils de Lyon, Pierre-Bénite, France; Immunogenomics and Inflammation Research Unit EA 4130, University of Lyon, Edouard Herriot Hospital, Lyon, France.
  • 5. Immunology Department, Lyon-Sud Hospital, Hospices Civils de Lyon, Pierre-Bénite, France.
  • 6. Université Paris-Est Créteil, Institut Mondor de Recherche Biomédicale, INSERM U955, Créteil, France; Département de Pathologie, Hôpitaux Universitaires Henri Mondor, Assistance publique des Hôpitaux de Paris, Créteil, France.
  • 7. Université Paris-Est Créteil, Institut Mondor de Recherche Biomédicale, INSERM U955, Créteil, France; Unité hémopathies lymphoïdes, Hôpitaux Universitaires Henri Mondor, Assistance publique des Hôpitaux de Paris, Créteil, France.
  • 8. Université Paris 5, Institut Necker-Enfants Malades (INEM), Institut National de Recherche Médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker-Enfants Malades, Paris, France.
  • 9. CRCL, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Faculté de Médecine Lyon Sud, Université Claude Bernard Lyon I, 69921 Oullins Cedex, France.
  • 10. CRCT, INSERM U1037 - Université Paul Sabatier - CNRS ERL5294, Université de Toulouse, Laboratoire d'Excellence TOUCAN, Programme Hospitalo-Universitaire en Cancérologie CAPTOR, Toulouse, France; IUCT, 31037 Toulouse, France.
  • 11. Université Côte d'Azur, INSERM, C3M, 06204 Nice, France; Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Department of Dermatology, 06204 Nice, France.
  • 12. Université Côte d'Azur, INSERM, C3M, 06204 Nice, France. Electronic address: [email protected].
  • 13. Université Côte d'Azur, INSERM, C3M, 06204 Nice, France; CIRI, Université de Lyon, INSERM U1111, ENS de Lyon, Université Lyon 1, CNRS, UMR 5308, 69007 Lyon, France. Electronic address: [email protected].
PMID: 31447347 DOI: 10.1016/j.ccell.2019.07.008
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.
Products