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. Epub 2019 Aug 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Cell Line, Tumor
  • Cell Lineage / immunology
  • Datasets as Topic
  • Disease Models, Animal
  • Female
  • Gene Knockdown Techniques
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / genetics
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / metabolism*
  • HEK293 Cells
  • Humans
  • Immunoblastic Lymphadenopathy / genetics
  • Immunoblastic Lymphadenopathy / pathology*
  • Lymphoma, T-Cell / drug therapy
  • Lymphoma, T-Cell / genetics
  • Lymphoma, T-Cell / immunology
  • Lymphoma, T-Cell / pathology*
  • Male
  • Mice, Transgenic
  • Middle Aged
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • NF-kappaB-Inducing Kinase
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism

Substances

  • NF-kappa B
  • Protein Kinase Inhibitors
  • GAPDH protein, human
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
  • Protein Serine-Threonine Kinases