Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell–derived lymphomas

Vallois, David; Dobay, Maria Pamela; Morin, Ryan D.; Lemonnier, François; Missiaglia, Edoardo; Juilland, Mélanie; Iwaszkiewicz, Justyna; Fataccioli, Virginie; Bisig, Bettina; Roberti, Annalisa; Grewal, Jasleen K.; Bruneau, Julie; Fabiani, Bettina; Martin, Antoine; Bonnet, Christophe; Michielin, Olivier; Jaı̈s, Jean-Philippe; Figeac, Martin; Bernard, Olivier A.; Delorenzi, Mauro; Haı̈oun, Corinne; Tournilhac, Olivier; Thome, Margot; Gascoyne, Randy D.; Gaulard, Philippe; Leval, Laurence de

doi:10.1182/blood-2016-02-698977

Cited by 258 publications

(319 citation statements)

References 58 publications

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“…The frequency of mutations in PTCL-NOS was significantly lower ( TET2, 17%; RHOA G17V, 0%; DNMT3A, 4%; IDH2, 0%). These results extend previous findings, demonstrating overlapping genetic characteristics in AITL and other PTCL of TFH origin, 13 including F-PTCL. To investigate the clustering of F-PTCL and TFH-like PTCL compared to AITL and PTCL-NOS, we performed principal component analysis (PCA) of the top 6000 most variably expressed genes based on gene expression profiles of 144 cases.…”

Section: 3supporting

confidence: 91%

“…Maria Pamela Dobay, 1 Francois Lemonnier, 2,3 Edoardo Missiaglia, 1,4 Christian Bastard, 5 David Vallois,4 Jean-Philippe Jais, 6 Laurianne Scourzic, 7 Aurélie Dupuy, 2,3 Virginie Fataccioli, 2,3,14 Anais Pujals, 2,3,14 Marie Parrens, 8 Fabien Le Bras, 9 Thérèse Rousset, 10 Jean-Michel Picquenot, 11 Nadine Martin, 2,3 Corinne Haioun, 2,3,9 Richard Delarue, 12 Olivier A. Bernard, 7 Mauro Delorenzi, 1,13 …”

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Integrative clinicopathological and molecular analyses of angioimmunoblastic T-cell lymphoma and other nodal lymphomas of follicular helper T-cell origin

et al. 2017

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Section: 3supporting

confidence: 91%

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Integrative clinicopathological and molecular analyses of angioimmunoblastic T-cell lymphoma and other nodal lymphomas of follicular helper T-cell origin

et al. 2017

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“…the G17V residue have been proposed as driver events in PTCL (13,21,22). Among these drivers, IDH2 mutations seem restricted to AITL, whereas TET2, DNMT3A, and RHOA mutations can be found in other PTCL entities as well, although they are enriched in PTCL of T FH origin (12,13,19,23). These findings suggest that epigenetic alteration is a hallmark of malignant transformation in AITL.…”

Section: Significancementioning

confidence: 98%

The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development

Lemonnier

Cairns

Inoue

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Oncogenic isocitrate dehydrogenase (IDH)1 and IDH2 mutations at three hotspot arginine residues cause an enzymatic gain of function that leads to the production and accumulation of the metabolite 2-hydroxyglutarate (2HG), which contributes to the development of a number of malignancies. In the hematopoietic system, mutations in IDH1 at arginine (R) 132 and in IDH2 at R140 and R172 are commonly observed in acute myeloid leukemia, and elevated 2HG is observed in cells and serum. However, in angioimmunoblastic T-cell lymphoma (AITL), mutations are almost exclusively restricted to IDH2 R172, and levels of 2HG have not been comprehensively measured. In this study, we investigate the expression pattern of mutant IDH2 in the AITL tumor microenvironment and measure levels of 2HG in tissue and serum of AITL patients. We find that mutant IDH2 expression is restricted to the malignant T-cell component of AITL, and that 2HG is elevated in tumor tissue and serum of patients. We also investigate the differences between the three hotspot mutation sites in IDH1 and IDH2 using conditional knock-in mouse models. These studies show that in the lymphoid system, mutations in IDH2 at R172 produce high levels of 2HG compared with mutations at the other two sites and that lymphoid development is impaired in these animals. These data provide evidence that IDH2 R172 mutations may be the only variants present in AITL because of their capacity to produce significant amounts of the oncometabolite 2HG in the cell of origin of this disease.isocitrate dehydrogenase | AITL | lymphoma | 2-hydroxyglutarate | T cell

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“…13,27 Intriguingly, p.K18N, confirmed to be an activating mutation, was reported in a few AITL samples. 48 Moreover, both active (p.C16R and p.G14V) and inactive (p.G17E and p.G17V) RHOA mutations were found in ATLL. 46 These observations suggest that the RHOA mutants may induce development of T-cell lymphomas through mechanisms other than classical RHOA signaling.…”

Section: Rhoa Mutationsmentioning

confidence: 99%

“…Half of the samples of AITL and nodal PTCL with TFH phenotype had mutations in genes encoding components of the T-cell Receptor (TCR) signaling pathway in an almost exclusive manner: 48 e.g., PLCgamma, 14%; 48 CD28, 9% -11%; 48,49 FYN, 3% -4%; 27,48 and VAV1 5%. 48 A substantial proportion of these mutations are commonly found in ATLL.…”

Section: Mutations In Components Of the T-cell Receptor (Tcr) Pathwaymentioning

confidence: 99%

Recent Progress in the Understanding of Angioimmunoblastic T-cell Lymphoma

Fujisawa

Sakata‐Yanagimoto

2017

J Clin Exp Hematopathol

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Angioimmunoblastic T-cell lymphoma (AITL) has been classified as a subtype of mature T-cell neoplasms. The recent revision of the WHO classification proposed a new category of nodal T-cell lymphoma with follicular helper T (TFH)-cell phenotype, which was classified into three diseases: AITL, follicular T-cell lymphoma, and nodal peripheral T-cell lymphoma with TFH phenotype. These lymphomas are defined by the expression of TFH-related antigens, CD279/PD-1, CD10, BCL6, CXCL13, ICOS, SAP, and CXCR5. Although recurrent mutations in TET2, IDH2, DNMT3A, RHOA, and CD28, as well as gene fusions, such as ITK-SYK and CTLA4-CD28, were not diagnostic criteria, they may be considered as novel criteria in the near future. Notably, premalignant mutations, tumor-specific mutations, and mutations specific to tumor-infiltrating B cells were identified in AITL. Thus, multi-step and multi-lineage genetic events may lead to the development of AITL.

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Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell–derived lymphomas

Abstract: Key Points A high frequency of diverse activating mutations in costimulatory/TCR-related signaling genes occurs in AITL and other TFH-derived PTCL. Deregulated TCR activation may play a role in the pathogenesis of TFH-derived PTCL, paving the way for developing novel targeted therapies.

Cited by 258 publications

References 58 publications

Integrative clinicopathological and molecular analyses of angioimmunoblastic T-cell lymphoma and other nodal lymphomas of follicular helper T-cell origin

Integrative clinicopathological and molecular analyses of angioimmunoblastic T-cell lymphoma and other nodal lymphomas of follicular helper T-cell origin

The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development

Recent Progress in the Understanding of Angioimmunoblastic T-cell Lymphoma

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