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

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

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

Journal

Cancer cell

ISSN: 1878-3686

Titre abrégé: Cancer Cell

Pays: United States

ID NLM: 101130617

Informations de publication

Date de publication:
16 09 2019

Historique:

received: 01 05 2018

revised: 17 04 2019

accepted: 26 07 2019

pubmed: 27 8 2019

medline: 19 5 2020

entrez: 27 8 2019

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ccell.2019.07.008 PMID: 31447347

pubmed: 31447347

pii: S1535-6108(19)30335-6

doi: 10.1016/j.ccell.2019.07.008

pii:

doi:

Substances chimiques

NF-kappa B 0

Protein Kinase Inhibitors 0

GAPDH protein, human EC 1.2.1.12

Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) EC 1.2.1.12

Protein Serine-Threonine Kinases EC 2.7.11.1

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

268-287.e10