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

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

doi:10.1016/j.ccell.2019.07.008

Cited by 35 publications

(34 citation statements)

References 98 publications

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“…Only very recently, in 2018 and 2019, three valid preclinical mouse models for AITL were engineered. Two mouse models 58,68 are based on genetic inactivation of Tet2 combined with overexpression of the mutated RhoA G17V and one model relies on overexpression of GAPDH in the T cell lineage 135 . These lymphoma mouse models closely mimicked AITL disease in terms of clinical, pathological, histological, transcriptional, genetic, and immunophenotypic features.…”

Section: Resultsmentioning

confidence: 99%

“…These lymphoma mouse models closely mimicked AITL disease in terms of clinical, pathological, histological, transcriptional, genetic, and immunophenotypic features. Moreover, these models allowed to reveal that AITL tumor were addicted to activation of signaling pathways such as mTOR 58,68 or NF-κB 135 and permitted to test successfully therapeutic options interfering with these pathways. This means that finally we can make use of these AITL preclinical mouse models to address questions otherwise still out of reach.…”

Section: Resultsmentioning

confidence: 99%

“…Activation of the noncanonical pathway depends on the activation of the NF-κB inducing kinase (NIK) and IKKα phosphorylation 141 . Mondragon et al 135 opted for a newly developed small-molecule inhibitor of NIK to interfere with this pathway (patent PCT/EP2017/ 067306; Fig. 5).…”

Section: Gapdh Overexpression In T-cell Lineage: Plck-gapdh Micementioning

confidence: 99%

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New preclinical models for angioimmunoblastic T-cell lymphoma: filling the GAP

et al. 2020

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Mouse models are essential to study and comprehend normal and malignant hematopoiesis. The ideal preclinical model should mimic closely the human malignancy. This means that these mice should recapitulate the clinical behavior of the human diseases such as cancer and therapeutic responses with high reproducibility. In addition, the genetic mutational status, the cell phenotype, the microenvironment of the tumor and the time until tumor development occurs, should be mimicked in a preclinical model. This has been particularly challenging for human angioimmunoblastic lymphoma (AITL), one of the most prominent forms of peripheral T-cell lymphomas. A complex network of interactions between AITL tumor cells and the various cells of the tumor microenvironment has impeded the study of AITL pathogenesis in vitro. Very recently, new mouse models that recapitulate faithfully the major features of human AITL disease have been developed. Here, we provide a summary of the pathology, the transcriptional profile and genetic and immune-phenotypic features of human AITL. In addition, we give an overview of preclinical models that recapitulate more or less faithfully human AITL characteristics and pathology. These recently engineered mouse models were essential in the evaluation of novel therapeutic agents for possible treatment of AITL, a malignancy in urgent need of new treatment options. Angioimmunoblastic T-cell lymphoma: a challenging complex malignancy Clinical aspects Angioimmunoblastic T-cell lymphoma (AITL) belongs since 2016 after revision of the world health organization (WHO) classification to the nodal T-cell lymphomas with follicular helper T-cell (Tfh) phenotype 1. AITL is a rare, aggressive lymphoma with little treatment options. Overall survival is generally poor with a five-year median survival rate of 32% 2,3. It represents only 1-2% of the non-Hodgkin's lymphomas. However, AITL appears to be the most prevalent PTCL, representing up to 35% of the noncutaneous peripheral T-cell lymphomas 2,4-6. AITL pathology develops late in life with a median age at onset of 59-65 years and patients display a generalized lymphoadenopathy 7,8. Seventy percent of the patients have bone marrow involvement and unfortunately early stage detection of AITL is very uncommon (10%) 9. Disease symptoms resemble closely an infection inducing immunologic hyper-activation (fever, rash, loss of weight, hemolytic anemia 2,5) (Fig. 1). AITL has particular clinical and pathological features, associated with splenomegaly, hepatomegaly and enlarged lymph nodes showing effacement of normal architecture and appearance of endothelial venules 3 (Fig. 1). Other typical clinical manifestation of AITL are cutaneous lesions also called skin rash in 20-50% of the patients and accumulation of abdominal ascites 5,10-13. These patients often test positive for autoimmunity including detection of rheumatoid factor, anti-smooth muscle, and nuclear autoantibodies 14. They also present a general increase in immunoglobulins called hypergammaglobulemia (30%) 7,12 .

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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New preclinical models for angioimmunoblastic T-cell lymphoma: filling the GAP

et al. 2020

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“…Another one of the interests is immune checkpoint inhibitors. In the vast majority of AITL, the neoplastic Tfh cells express PD1, which may play a role for the Tfh cell migration [59] or NFκB activation in PDL1-expressing B cells [98]. Therefore, the significance of the blockade of PD1-PDL1 ligation in AITL may be different from the usual immune checkpoint inhibition in other neoplasms.…”

Section: Immune Checkpoint Inhibitorsmentioning

confidence: 99%

“…NIK inhibitors are already referred to [98]. Duvelisib, a PI3Kδ inhibitor that blocks ICOS-PI3K pathway, may be a candidate [77].…”

Section: Other Possibilitiesmentioning

confidence: 99%

Advances in understanding of angioimmunoblastic T-cell lymphoma

2020

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It has been nearly half a century since angioimmunoblastic T-cell lymphoma (AITL) was characterized in the early 1970’s. Our understanding of the disease has dramatically changed due to multiple discoveries and insights. One of the key features of AITL is aberrant immune activity. Although AITL is now understood to be a neoplastic disease, pathologists appreciated that it was an inflammatory condition. The more we understand AITL at cellular and genetic levels, the more we view it as both a neoplastic and an inflammatory disease. Here, we review recent progress in our understanding of AITL, focusing on as yet unsolved questions.

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Characterization of the spectrum of trivalent VAV1‐mutation‐driven tumours using a gene‐edited mouse model

et al. 2022

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Mutations in the VAV1 guanine nucleotide exchange factor 1 have been recently found in peripheral T cell lymphoma and nonsmall‐cell lung cancer (NSCLC). To understand their pathogenic potential, we generated a gene‐edited mouse model that expresses a VAV1 mutant protein that recapitulates the signalling alterations present in the VAV1 mutant subclass most frequently found in tumours. We could not detect any overt tumourigenic process in those mice. However, the concurrent elimination of the Trp53 tumour suppressor gene in them drives T cell lymphomagenesis. This process represents an exacerbation of the normal functions that wild‐type VAV1 plays in follicular helper T cells. We also found that, in combination with the Kras oncogene, the VAV1 mutant version favours progression of NSCLC. These data indicate that VAV1 mutations play critical, although highly cell‐type‐specific, roles in tumourigenesis. They also indicate that such functions are contingent on the mutational landscape of the tumours involved.

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

Abstract: Highlights d Overexpression of GAPDH in T cell lineage in a mouse model recapitulates AITL disease d AITL tumors are characterized by a GAPDH induction of the NF-kB pathway d plck-GAPDH mice allow to model AITL disease for testing of new therapeutic strategies

Cited by 35 publications

References 98 publications

New preclinical models for angioimmunoblastic T-cell lymphoma: filling the GAP

New preclinical models for angioimmunoblastic T-cell lymphoma: filling the GAP

Advances in understanding of angioimmunoblastic T-cell lymphoma

Characterization of the spectrum of trivalent VAV1‐mutation‐driven tumours using a gene‐edited mouse model

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