35 results on '"Fataccioli V"'
Search Results
2. ALK-negative anaplastic large cell lymphoma with DUSP22 rearrangement has distinctive disease characteristics with better progression-free survival: a LYSA study
- Author
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Sibon, D., Bisig, B., Bonnet, C., Poullot, E., Bachy, E., Cavalieri, D., Fataccioli, V., Bregnard, C., Drieux, F., Bruneau, J., Lemonnier, F., Dupuy, A., Bossard, C., Parrens, M., Bouabdallah, K., Ketterer, N., Berthod, G., Cairoli, A., Damaj, G., Tournilhac, O., Jais, J.P., Gaulard, P., and De Leval, L.
- Subjects
Hematology - Abstract
ALK-negative anaplastic large cell lymphoma (ALCL) comprises subgroups harboring rearrangements of DUSP22 (DUSP22- R) or TP63 (TP63-R). Two studies reported 90% and 40% 5-year overall survival (OS) rates in 21 and 12 DUSP22-R/TP63- not rearranged (NR) patients, respectively, making the prognostic impact of DUSP22-R unclear. Here, 104 newly diagnosed ALK-negative ALCL patients (including 37 from first-line clinical trials) from the LYSA TENOMIC database were analyzed by break-apart fluorescence in situ hybridization assays for DUSP22-R and TP63-R. There were 47/104 (45%) DUSP22-R and 2/93 (2%) TP63-R cases, including one DUSP22-R/TP63-R case. DUSP22-R tumors more frequently showed CD3 expression (62% vs. 35%, P=0.01), and less commonly a cytotoxic phenotype (27% vs. 82%; P
- Published
- 2022
3. IMPACT OF DUSP22 REARRANGEMENT ON THE PROGNOSIS OF SYSTEMIC ALK‐NEGATIVE ANAPLASTIC LARGE CELL LYMPHOMA: A LYSA AND TENOMIC STUDY
- Author
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Sibon, D, primary, Bisig, B, additional, Bonnet, C, additional, Bachy, E, additional, Cavalieri, D, additional, Fataccioli, V, additional, Drieux, F, additional, Bruneau, J, additional, Lemonnier, F, additional, Bossard, C, additional, Bouabdallah, K, additional, Parrens, M, additional, Damaj, G, additional, Tournilhac, O, additional, Jais, J. P, additional, Gaulard, P, additional, and de Leval, L, additional
- Published
- 2021
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4. MONOMORPHIC EPITHELIOTROPIC INTESTINAL T‐CELL LYMPHOMA (MEITL): CLINICO‐PATHOLOGICAL ANALYSIS OF A MULTICENTER EUROPEAN COHORT
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Cavalieri, D., primary, Tournilhac, O., additional, Missiglia, E., additional, Bonnet, C., additional, Ledoux‐Pilon, A., additional, Bisig, B., additional, Cairoli, A., additional, Poullot, E., additional, Fataccioli, V., additional, Parrens, M., additional, Copin, M. C., additional, Gutierrez, F. Llamas, additional, Xerri, L., additional, Bossard, C., additional, Wind, R., additional, Drieux, F., additional, Lhomme, F., additional, Daniel, A., additional, Clément‐Filliatre, L., additional, Lemmonier, F., additional, Morel, P., additional, Noël, R., additional, Brotelle, T., additional, Glaisner, S., additional, Sibon, D., additional, Yamani, A., additional, Bologna, S., additional, Queru, K., additional, Damaj, G., additional, Letailleur, V., additional, Villemagne, B., additional, Fleck, E., additional, Dupont, E., additional, Tchernonog, E., additional, Monjanel, H., additional, Wilde, V., additional, Vallois, D., additional, Gaulard, P., additional, and Leval, L., additional
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- 2021
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5. JAK-STAT PATHWAY AND EPIGENETIC REGULATORS ARE CRITICAL PLAYERS IN BI-ALCL PATHOGENESIS?
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Laurent, C., primary, Nicolae, A., additional, Laurent, C., additional, Le Bras, F., additional, Haioun, C., additional, Fataccioli, V., additional, Amara, N., additional, Adélaïde, J., additional, Guille, A., additional, Schiano De Colella, J., additional, Tesson, B., additional, Traverse-Glehen, A., additional, Chenard, M., additional, Mescam, L., additional, Moreau, A., additional, Chassagne-Clément, C., additional, Somja, J., additional, Escudié, F., additional, André, M., additional, Martin, N., additional, Hamy-Petit, A., additional, Reyal, F., additional, Croix, M., additional, Birnbaum, D., additional, Brousset, P., additional, Xerri, L., additional, and Gaulard, P., additional
- Published
- 2019
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6. Integrative clinicopathological and molecular analyses of angioimmunoblastic T-cell lymphoma and other nodal lymphomas of follicular helper T-cell origin
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Dobay, M.P., Lemonnier, F., Missiaglia, E., Bastard, C., Vallois, D., Jais, J.P., Scourzic, L., Dupuy, A., Fataccioli, V., Pujals, A., Parrens, M., Le Bras, F., Rousset, T., Picquenot, J.M., Martin, N., Haioun, C., Delarue, R., Bernard, O.A., Delorenzi, M., de Leval, L., Gaulard, P., Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Groupe d'étude des proliférations lymphoïdes ( GPL ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Hôpital Haut-Lévêque, Université Sciences et Technologies - Bordeaux 1-CHU Bordeaux [Bordeaux], Institut Gustave Roussy ( IGR ), Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), CHU Bordeaux [Bordeaux], CHU Henri Mondor, Université Paris-Est Créteil Val-de-Marne - Faculté de médecine ( UPEC Médecine ), Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Laboratoire des Adaptations Physiologiques aux Activités Physiques ( LAPHAP ), Université de Poitiers, Service de Pathologie Clinique, Université de Lausanne ( UNIL ) -Centre Hospitalier Universitaire Vaudois [Lausanne] ( CHUV ) -Institut Universitaire de Pathologie, Institut Mondor de Recherche Biomédicale ( IMRB ), and Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 )
- Subjects
Male ,[ SDV.CAN ] Life Sciences [q-bio]/Cancer ,DNA Methyltransferase 3A ,Dioxygenases ,Diagnosis, Differential ,Proto-Oncogene Proteins ,Terminology as Topic ,Humans ,DNA (Cytosine-5-)-Methyltransferases ,Online Only Articles ,Lymphoma, Follicular ,ComputingMilieux_MISCELLANEOUS ,Aged ,Lymphoma, T-Cell, Peripheral ,Dendritic Cells ,T-Lymphocytes, Helper-Inducer ,Middle Aged ,Survival Analysis ,Isocitrate Dehydrogenase ,DNA-Binding Proteins ,Eosinophils ,Gene Expression Regulation, Neoplastic ,Immunoblastic Lymphadenopathy ,Mutation ,Female ,rhoA GTP-Binding Protein - Abstract
International audience
- Published
- 2017
7. TANSLOCATIONS INVOLVING CD28 ARE RARE IN PERIPHERAL T-CELL LYMPHOMAS
- Author
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Vallois, D., primary, Dupuy, A., additional, Lemonnier, F., additional, Fataccioli, V., additional, Ortonne, N., additional, Allen, G., additional, Tournilhac, O., additional, Delarue, R., additional, Rousselet-Chapeau, M., additional, Fabiani, B., additional, Llamas-Gutierrez, F., additional, Ko, Y.H., additional, Kataoka, K., additional, Gaulard, P., additional, and de Leval, L., additional
- Published
- 2017
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8. GENE EXPRESSION PROFILING USING a RTMLPA ASSAY ALLOWS FOR AN ACCURATE CLASSIFICATION OF PERIPHERAL T-CELL LYMPHOMA AND HIGHLIGHTS NOVEL SUBGROUPS WITHIN PTCLS-NOS
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Ruminy, P., primary, Drieux, F., additional, Abdel Sater, A., additional, Fataccioli, V., additional, Marchand, V., additional, Parrens, M., additional, Bossard, C., additional, Dobay, P., additional, Viailly, P., additional, Veresezan, L., additional, Dupuy, A., additional, Pujals, A., additional, Picquenot, J., additional, Tilly, H., additional, De Leval, L., additional, Jardin, F., additional, and Gaulard, P., additional
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- 2017
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9. INTEGRATIVE ANALYSIS OF FEATURES ASSOCIATED WITH TET2, IDH2, DNMT3A, AND RHOA MUTATIONS IN ANGIOIMMUNOBLASTIC T CELL LYMPHOMA: A LYSA STUDY
- Author
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Lemonnier, F., primary, Safar, V., additional, Cottereau, A., additional, Fataccioli, V., additional, Chaillol, I., additional, Pelletier, R., additional, Letourneau, A., additional, Dupuy, A., additional, Bossard, C., additional, Martin, A., additional, Robe, C., additional, Pelletier, L., additional, Pujals, A., additional, Bachy, E., additional, Delmer, A., additional, Moles Moreau, M., additional, Tilly, H., additional, Parrens, M., additional, Delfau-Larue, M., additional, Missiaglia, E., additional, Meignan, M., additional, de Leval, L., additional, Haioun, C., additional, and Gaulard, P., additional
- Published
- 2017
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10. SERUM 2-HYDROXYGLUTARATE, A PREDICTIVE BIOMARKER OF THE PRESENCE OF IDH2 MUTATIONS IN AITL PATIENTS
- Author
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Broutin, S., primary, Dupuy, A., additional, Koscielny, S., additional, Fataccioli, V., additional, Lemonnier, F., additional, de Leval, L., additional, Robe, C., additional, Pujals, A., additional, Safar, V., additional, Delarue, R., additional, Delfau-Larue, M.H., additional, Ribrag, V., additional, Haioun, C., additional, Gaulard, P., additional, and Paci, A., additional
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- 2017
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11. Angioimmunoblastic T-cell lymphoma is the most common T-cell lymphoma in two distinct French information data sets
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de Leval, L., primary, Parrens, M., additional, Le Bras, F., additional, Jais, J.-P., additional, Fataccioli, V., additional, Martin, A., additional, Lamant, L., additional, Delarue, R., additional, Berger, F., additional, Arbion, F., additional, Bossard, C., additional, Copin, M.-C., additional, Canioni, D., additional, Charlotte, F., additional, Damaj, G., additional, Dartigues, P., additional, Fabiani, B., additional, Ledoux-Pilon, A., additional, Montagne, K., additional, Molina, T., additional, Patey, M., additional, Tas, P., additional, Peoch, M., additional, Petit, B., additional, Petrella, T., additional, Picquenot, J.-M., additional, Rousset, T., additional, Rousselet, M.-C., additional, Soubeyran, I., additional, Thiebault, S., additional, Tournilhac, O., additional, Xerri, L., additional, Gisselbrecht, C., additional, Haioun, C., additional, Delsol, G., additional, and Gaulard, P., additional
- Published
- 2015
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12. PD‐1 BLOCKADE IN A FRENCH SERIES OF 13 RELAPSED / REFRACTORY NK/T‐CELL LYMPHOMA PATIENTS.
- Author
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Couronné, L., Chaubard, S., Bruneau, J., Laurent, C., Rossignol, J., Suarez, F., Moignet Autrel, A., Clavert, A., Duléry, R., Alexis, M., Lemonnier, F., Noël, R., Tardy, S., Gaulard, P., Fataccioli, V., Kataoka, K., Ghesquières, H., Salles, G., Bachy, E., and Hermine, O.
- Subjects
APOPTOSIS - Published
- 2019
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13. INTEGRATIVE ANALYSIS OF FEATURES ASSOCIATED WITH TET2, IDH2, DNMT3 A, AND RHOA MUTATIONS IN ANGIOIMMUNOBLASTIC T CELL LYMPHOMA: A LYSA STUDY.
- Author
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Lemonnier, F., Safar, V., Cottereau, A., Fataccioli, V., Chaillol, I., Pelletier, R., Letourneau, A., Dupuy, A., Bossard, C., Martin, A., Robe, C., Pelletier, L., Pujals, A., Bachy, E., Delmer, A., Moles Moreau, M., Tilly, H., Parrens, M., Delfau ‐ Larue, M., and Missiaglia, E.
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- 2017
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14. Lack of SMARCB1 expression characterizes a subset of human and murine peripheral T-cell lymphomas.
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Fischer A, Albert TK, Moreno N, Interlandi M, Mormann J, Glaser S, Patil P, de Faria FW, Richter M, Verma A, Balbach ST, Wagener R, Bens S, Dahlum S, Göbel C, Münter D, Inserte C, Graf M, Kremer E, Melcher V, Di Stefano G, Santi R, Chan A, Dogan A, Bush J, Hasselblatt M, Cheng S, Spetalen S, Fosså A, Hartmann W, Herbrüggen H, Robert S, Oyen F, Dugas M, Walter C, Sandmann S, Varghese J, Rossig C, Schüller U, Tzankov A, Pedersen MB, d'Amore FA, Mellgren K, Kontny U, Kancherla V, Veloza L, Missiaglia E, Fataccioli V, Gaulard P, Burkhardt B, Soehnlein O, Klapper W, de Leval L, Siebert R, and Kerl K
- Subjects
- Animals, Humans, Mice, Female, Cell Line, Tumor, Male, Vorinostat pharmacology, Single-Cell Analysis, SMARCB1 Protein genetics, SMARCB1 Protein metabolism, Lymphoma, T-Cell, Peripheral genetics, Lymphoma, T-Cell, Peripheral drug therapy, Lymphoma, T-Cell, Peripheral metabolism, Lymphoma, T-Cell, Peripheral pathology, Histone Deacetylase Inhibitors pharmacology, Tumor Microenvironment genetics, Tumor Microenvironment drug effects, DNA Methylation, Gene Expression Regulation, Neoplastic
- Abstract
Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Here, we identify a subgroup, PTCL-NOS
SMARCB1- , which is characterized by the lack of the SMARCB1 protein and occurs more frequently in young patients. Human and murine PTCL-NOSSMARCB1- show similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development. Single-cell analyses of human and murine tumors revealed a rich and complex network of interactions between tumor cells and an immunosuppressive and exhausted tumor microenvironment (TME). In a drug screen, we identified histone deacetylase inhibitors (HDACi) as a class of drugs effective against PTCL-NOSSmarcb1- . In vivo treatment of mouse tumors with SAHA, a pan-HDACi, triggered remodeling of the TME, promoting replenishment of lymphoid compartments and reversal of the exhaustion phenotype. These results provide a rationale for further exploration of HDACi combination therapies targeting PTCL-NOSSMARCB1- within the TME., (© 2024. The Author(s).)- Published
- 2024
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15. Comprehensive Genetic Profiling Reveals Frequent Alterations of Driver Genes on the X Chromosome in Extranodal NK/T-cell Lymphoma.
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Ito Y, Marouf A, Kogure Y, Koya J, Liévin R, Bruneau J, Tabata M, Saito Y, Shingaki S, Yuasa M, Yamaguchi K, Murakami K, Weil R, Vavasseur M, Andrieu GP, Latiri M, Veleanu L, Dussiot M, André I, Joshi A, Lagresle-Peyrou C, Magerus A, Chaubard S, Lavergne D, Bachy E, Brunet E, Fataccioli V, Brouzes C, Laurent C, de Leval L, Traverse-Glehen A, Bossard C, Parrens M, Meignin V, Philippe L, Rossignol J, Suarez F, Michot JM, Tournilhac O, Damaj G, Lemonnier F, Bôle-Feysot C, Nitschké P, Tesson B, Laurent C, Molina T, Asnafi V, Watatani Y, Chiba K, Okada A, Shiraishi Y, Tsukita S, Izutsu K, Miyoshi H, Ohshima K, Sakata S, Dobashi A, Takeuchi K, Sanada M, Gaulard P, Jaccard A, Ogawa S, Hermine O, Kataoka K, and Couronné L
- Subjects
- Humans, Male, Female, DNA Copy Number Variations, Mutation, Middle Aged, Animals, Adult, Mice, Prognosis, Aged, Gene Expression Profiling, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Young Adult, Epstein-Barr Virus Infections genetics, Epstein-Barr Virus Infections virology, Epstein-Barr Virus Infections complications, Chromosomes, Human, X genetics, Lymphoma, Extranodal NK-T-Cell genetics, Lymphoma, Extranodal NK-T-Cell virology, Lymphoma, Extranodal NK-T-Cell pathology, Lymphoma, Extranodal NK-T-Cell metabolism
- Abstract
Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related neoplasm with male dominance and a poor prognosis. A better understanding of the genetic alterations and their functional roles in ENKTCL could help improve patient stratification and treatments. In this study, we performed a comprehensive genetic analysis of 178 ENKTCL cases to delineate the landscape of mutations, copy number alterations (CNA), and structural variations, identifying 34 driver genes including six previously unappreciated ones, namely, HLA-B, HLA-C, ROBO1, CD58, POT1, and MAP2K1. Among them, CD274 (24%) was the most frequently altered, followed by TP53 (20%), CDKN2A (19%), ARID1A (15%), HLA-A (15%), BCOR (14%), and MSN (14%). Chromosome X losses were the most common arm-level CNAs in females (∼40%), and alterations of four X-linked driver genes (MSN, BCOR, DDX3X, and KDM6A) were more frequent in males and females harboring chromosome X losses. Among X-linked drivers, MSN was the most recurrently altered, and its expression was lost in approximately one-third of cases using immunohistochemical analysis. Functional studies of human cell lines showed that MSN disruption promoted cell proliferation and NF-κB activation. Moreover, MSN inactivation increased sensitivity to NF-κB inhibition in vitro and in vivo. In addition, recurrent deletions were observed at the origin of replication in the EBV genome (6%). Finally, by integrating the 34 drivers and 19 significant arm-level CNAs, nonnegative matrix factorization and consensus clustering identified two molecular groups with different genetic features and prognoses irrespective of clinical prognostic factors. Together, these findings could help improve diagnostic and therapeutic strategies in ENKTCL. Significance: Integrative genetic analyses and functional studies in extranodal NK/T-cell lymphoma identify frequent disruptions of X-linked drivers, reveal prognostic molecular subgroups, and uncover recurrent MSN alterations that confer sensitivity to NF-κB inhibition., (©2024 American Association for Cancer Research.)
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- 2024
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16. Clinical and histological study of follicular helper T-cell lymphomas with indolent evolution.
- Author
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Messéant O, Drieux F, Sako N, Fataccioli V, Camus V, Robe C, Houot R, Tas P, Llamas-Gutierrez F, Lamaison C, Abraham J, Delage-Corre M, Benguerfi S, Bossard JB, Gaulard P, and Lemonnier F
- Subjects
- Adult, Humans, Mutation, Steroids, T Follicular Helper Cells pathology, Lymphoma, Lymphoma, T-Cell drug therapy, Lymphoma, T-Cell genetics, Lymphoma, T-Cell pathology
- Abstract
Introduction: Follicular helper T-cell lymphomas (TFHL) have an aggressive course with a poor outcome. European and US guidelines recommend anthracycline-based chemotherapy as a first-line treatment, but the 5-year overall survival rate is still approximately 30%. We describe here the features of a cohort of TFHL patients who experienced prolonged survival despite the absence of specific treatment or the initiation of steroid-based therapy., Patients and Methods: In our study, we describe 15 adult patients who suffered from TFHL and had not received intensive chemotherapy at diagnosis for any reason. Biopsies of these cases were centrally reviewed, and the mutational pattern was determined using next-generation sequencing., Results: These 15 patients had the classic clinical, biological and pathological features of TFHL, angioimmunoblastic-type. TET2 mutations were found in 83% of patients; RHOA G17V, IDH2 R172 and DNMT3A mutations were found in 67%, 42% and 33% of the patients, respectively. Among the 15 patients, 8 did not receive any treatment, and 7 received steroid-based treatment. Ten patients had progression (5 in each group). Four patients died (3 of them from the progression of their lymphoma). The median follow-up in our cohort was 53 months. The 5-year OS was 66%, 100% for untreated patients and 29% for the others. In those 2 groups, the median time to treatment initiation was 22 months from diagnosis., Conclusion: We described a series of 15 well-characterized TFHL patients with an indolent outcome, suggesting that a watch-and-wait approach can be proposed in selected patients. Identifying factors predicting such evolution is warranted., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2024
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17. ALK-negative anaplastic large cell lymphoma with DUSP22 rearrangement has distinctive disease characteristics with better progression-free survival: a LYSA study.
- Author
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Sibon D, Bisig B, Bonnet C, Poullot E, Bachy E, Cavalieri D, Fataccioli V, Bregnard C, Drieux F, Bruneau J, Lemonnier F, Dupuy A, Bossard C, Parrens M, Bouabdallah K, Ketterer N, Berthod G, Cairoli A, Damaj G, Tournilhac O, Jais JP, Gaulard P, and De Leval L
- Subjects
- Humans, Anaplastic Lymphoma Kinase genetics, Brentuximab Vedotin therapeutic use, Disease-Free Survival, In Situ Hybridization, Fluorescence, Receptor Protein-Tyrosine Kinases genetics, Lymphoma, Large-Cell, Anaplastic diagnosis, Lymphoma, Large-Cell, Anaplastic drug therapy, Lymphoma, Large-Cell, Anaplastic genetics
- Abstract
ALK-negative anaplastic large cell lymphoma (ALCL) comprises subgroups harboring rearrangements of DUSP22 (DUSP22- R) or TP63 (TP63-R). Two studies reported 90% and 40% 5-year overall survival (OS) rates in 21 and 12 DUSP22-R/TP63- not rearranged (NR) patients, respectively, making the prognostic impact of DUSP22-R unclear. Here, 104 newly diagnosed ALK-negative ALCL patients (including 37 from first-line clinical trials) from the LYSA TENOMIC database were analyzed by break-apart fluorescence in situ hybridization assays for DUSP22-R and TP63-R. There were 47/104 (45%) DUSP22-R and 2/93 (2%) TP63-R cases, including one DUSP22-R/TP63-R case. DUSP22-R tumors more frequently showed CD3 expression (62% vs. 35%, P=0.01), and less commonly a cytotoxic phenotype (27% vs. 82%; P<0.001). At diagnosis, DUSP22- R ALCL patients more frequently had bone involvement (32% vs. 13%, P=0.03). The patient with DUSP22-R/TP63-R ALCL had a rapidly fatal outcome. After a median follow-up of 4.9 years, 5-year progression-free survival (PFS) and OS rates of 84 patients without TP63-R treated with curative-intent anthracycline-based chemotherapy were 41% and 53%, respectively. According to DUSP22 status, 5-year PFS was 57% for 39 DUSP22-R versus 26% for 45 triple-negative (DUSP22-NR/TP63-NR/ALK-negative) patients (P=0.001). The corresponding 5-year OS rates were 65% and 41%, respectively (P=0.07). In multivariate analysis, performance status and DUSP22 status significantly affected PFS, and distinguished four risk groups, with 4-year PFS and OS ranging from 17% to 73% and 21% to 77%, respectively. Performance status but not DUSP22 status influenced OS. The use of brentuximab vedotin in relapsed/refractory patients improved OS independently of DUSP22 status. Our findings support the biological and clinical distinctiveness of DUSP22- R ALK-negative ALCL. Its relevance to outcome in patients receiving frontline brentuximab vedotin remains to be determined.
- Published
- 2023
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18. Monomorphic epitheliotropic intestinal T-cell lymphoma comprises morphologic and genomic heterogeneity impacting outcome.
- Author
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Veloza L, Cavalieri D, Missiaglia E, Ledoux-Pilon A, Bisig B, Pereira B, Bonnet C, Poullot E, Quintanilla-Martinez L, Dubois R, Llamas-Gutierrez F, Bossard C, De Wind R, Drieux F, Fontaine J, Parrens M, Sandrini J, Fataccioli V, Delfau-Larue MH, Daniel A, Lhomme F, Clément-Filliatre L, Lemonnier F, Cairoli A, Morel P, Glaisner S, Joly B, El Yamani A, Laribi K, Bachy E, Siebert R, Vallois D, Gaulard P, Tournilhac O, and De Leval L
- Subjects
- Male, Female, Humans, Aged, Genomics, Mutation, Signal Transduction, Enteropathy-Associated T-Cell Lymphoma genetics, Enteropathy-Associated T-Cell Lymphoma metabolism, Enteropathy-Associated T-Cell Lymphoma pathology
- Abstract
Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare aggressive T-cell lymphoma most reported in Asia. We performed a comprehensive clinical, pathological and genomic study of 71 European MEITL patients (36 males, 35 females, median age 67 years). The majority presented with gastrointestinal involvement and had emergency surgery, and 40% had stage IV disease. The tumors were morphologically classified into two groups: typical (58%) and atypical (i.e., non-monomorphic or with necrosis, angiotropism or starry-sky pattern) (42%), sharing a homogeneous immunophenotypic profile (CD3+ [98%] CD4- [94%] CD5- [97%] CD7+ [97%] CD8+ [90%] CD56+ [86%] CD103+ [80%] cytotoxic marker+ [98%]) with more frequent expression of TCRgd (50%) than TCRab (32%). MYC expression (30% of cases) partly reflecting MYC gene locus alterations, correlated with non-monomorphic cytology. Almost all cases (97%) harbored deleterious mutation(s) and/or deletion of the SETD2 gene and 90% had defective H3K36 trimethylation. Other frequently mutated genes were STAT5B (57%), JAK3 (50%), TP53 (35%), JAK1 (12.5%), BCOR and ATM (11%). Both TP53 mutations and MYC expression correlated with atypical morphology. The median overall survival (OS) of 63 patients (43/63 only received chemotherapy after initial surgery) was 7.8 months. Multivariate analysis found a strong negative impact on outcome of MYC expression, TP53 mutation, STAT5B mutation and poor performance status while aberrant B-cell marker expression (20% of cases) correlated with better survival. In conclusion, MEITL is an aggressive disease with resistance to conventional therapy, predominantly characterized by driver gene alterations deregulating histone methylation and JAK/STAT signaling and encompasses genetic and morphologic variants associated with very high clinical risk.
- Published
- 2023
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19. Lymph node excisions provide more precise lymphoma diagnoses than core biopsies: a French Lymphopath network survey.
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Syrykh C, Chaouat C, Poullot E, Amara N, Fataccioli V, Parrens M, Traverse-Glehen A, Molina TJ, Xerri L, Martin L, Dubois R, Lacheretz-Szablewski V, Copin MC, Moreau A, Chenard MP, Cabarrou B, Lusque A, Gaulard P, Brousset P, and Laurent C
- Subjects
- Humans, Female, Biopsy, Large-Core Needle methods, Lymph Node Excision, Lymph Nodes surgery, Lymph Nodes pathology, Biopsy, Retrospective Studies, Multicenter Studies as Topic, Lymphoma diagnosis, Lymphoma surgery, Lymphoma pathology, Breast Neoplasms pathology
- Abstract
According to expert guidelines, lymph node surgical excision is the standard of care for lymphoma diagnosis. However, core needle biopsy (CNB) has become widely accepted as part of the lymphoma diagnostic workup over the past decades. The aim of this study was to present the largest multicenter inventory of lymph nodes sampled either by CNB or surgical excision in patients with suspected lymphoma and to compare their diagnostic performance in routine pathologic practice. We reviewed 32 285 cases registered in the French Lymphopath network, which provides a systematic expert review of all lymphoma diagnoses in France, and evaluated the percentage of CNB and surgical excision cases accurately diagnosed according to the World Health Organization classification. Although CNB provided a definitive diagnosis in 92.3% and seemed to be a reliable method of investigation for most patients with suspected lymphoma, it remained less conclusive than surgical excision, which provided a definitive diagnosis in 98.1%. Discordance rates between referral and expert diagnoses were higher on CNB (23.1%) than on surgical excision (21.2%; P = .004), and referral pathologists provided more cases with unclassified lymphoma or equivocal lesion through CNB. In such cases, expert review improved the diagnostic workup by classifying ∼90% of cases, with higher efficacy on surgical excision (93.3%) than CNB (81.4%; P < 10-6). Moreover, diagnostic concordance for reactive lesions was higher on surgical excision than CNB (P = .009). Overall, although CNB accurately diagnoses lymphoma in most instances, it increases the risk of erroneous or nondefinitive conclusions. This large-scale survey also emphasizes the need for systematic expert review in cases of lymphoma suspicion, especially in those sampled by using CNB., (© 2022 by The American Society of Hematology.)
- Published
- 2022
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20. Nodal cytotoxic peripheral T-cell lymphoma occurs frequently in the clinical setting of immunodysregulation and is associated with recurrent epigenetic alterations.
- Author
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Nicolae A, Bouilly J, Lara D, Fataccioli V, Lemonnier F, Drieux F, Parrens M, Robe C, Poullot E, Bisig B, Bossard C, Letourneau A, Missiaglia E, Bonnet C, Szablewski V, Traverse-Glehen A, Delfau-Larue MH, de Leval L, and Gaulard P
- Subjects
- Epigenesis, Genetic, Female, Herpesvirus 4, Human genetics, Humans, Male, Middle Aged, Receptors, Antigen, T-Cell, alpha-beta genetics, Receptors, Antigen, T-Cell, alpha-beta metabolism, Epstein-Barr Virus Infections, Lymphoma, T-Cell, Peripheral pathology
- Abstract
Nodal peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) with cytotoxic phenotype is overall rare, with most reports coming from Asia. Given its elusive pathobiology, we undertook a clinicopathological and molecular study of 54 Western patients diagnosed with PTCL, NOS expressing cytotoxic molecules, within a lymph node. More commonly males (M/F-2,6/1) with median age of 60 years were affected. Besides lymphadenopathy, 87% of patients had ≥1 involved extranodal site. High-stage disease (III-IV), International Prognostic Index >2, B symptoms, LDH level, and cytopenia(s) were observed in 92, 63, 67, 78, and 66% of cases, respectively. Ten patients had a history of B-cell malignancies, one each of myeloid neoplasm, breast or prostate cancer, and 4 others had underlying immune disorders. Most patients (70%) died, mostly of disease, with a median overall survival of 12.7 months. Immunophenotypically, the neoplastic lymphocytes were T-cell receptor (TCR) αβ + (47%), TCR-silent (44%) or TCRγδ+ (10%), commonly CD8 + (45%) or CD4-CD8- (32%). All except one had an activated cytotoxic profile, and 95% were subclassified into PTCL-TBX21 subtype based on CXCR3, TBX21, and GATA3 expression pattern. Seven patients (13%) disclosed EBER + tumor cells. Targeted DNA deep-sequencing (33 cases) and multiplex ligation-dependent reverse transcription-polymerase chain reaction assay (43 cases) identified frequent mutations in epigenetic modifiers (73%), including TET2 (61%) and DNMT3A (39%), recurrent alterations affecting the TCR (36%) and JAK/STAT (24%) signaling pathways and TP53 mutations (18%). Fusion transcripts involving VAV1 were identified in 6/43 patients (14%). Patients with nodal cytotoxic PTCL, NOS have an aggressive behavior and frequently present in a background of impaired immunity, although the association with Epstein-Barr virus is rare. The recurrent alterations in genes involved in DNA methylation together with genes related to cytokine or TCR signaling, suggest that co-operation of epigenetic modulation with cell-signaling pathways plays a critical role in the pathogeny of these lymphomas., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)
- Published
- 2022
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21. Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma.
- Author
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Liang HC, Costanza M, Prutsch N, Zimmerman MW, Gurnhofer E, Montes-Mojarro IA, Abraham BJ, Prokoph N, Stoiber S, Tangermann S, Lobello C, Oppelt J, Anagnostopoulos I, Hielscher T, Pervez S, Klapper W, Zammarchi F, Silva DA, Garcia KC, Baker D, Janz M, Schleussner N, Fend F, Pospíšilová Š, Janiková A, Wallwitz J, Stoiber D, Simonitsch-Klupp I, Cerroni L, Pileri S, de Leval L, Sibon D, Fataccioli V, Gaulard P, Assaf C, Knörr F, Damm-Welk C, Woessmann W, Turner SD, Look AT, Mathas S, Kenner L, and Merkel O
- Subjects
- Animals, Basic-Leucine Zipper Transcription Factors metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Gene Expression Regulation, Neoplastic, Humans, Immunoconjugates pharmacology, Interleukin-15 pharmacology, Interleukin-2 pharmacology, Interleukin-2 Receptor alpha Subunit genetics, Interleukin-2 Receptor alpha Subunit immunology, Interleukin-2 Receptor alpha Subunit metabolism, Ki-1 Antigen genetics, Ki-1 Antigen metabolism, Lymphoma, Large-Cell, Anaplastic drug therapy, Lymphoma, Large-Cell, Anaplastic metabolism, Lymphoma, Large-Cell, Anaplastic pathology, Mice, Receptors, Interleukin-2 immunology, Receptors, Interleukin-2 metabolism, Regulatory Sequences, Nucleic Acid, Repressor Proteins metabolism, Signal Transduction drug effects, Xenograft Model Antitumor Assays, Basic-Leucine Zipper Transcription Factors genetics, Lymphoma, Large-Cell, Anaplastic genetics, Receptors, Interleukin-2 genetics, Repressor Proteins genetics
- Abstract
Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL., (© 2021. The Author(s).)
- Published
- 2021
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22. Detection of Gene Fusion Transcripts in Peripheral T-Cell Lymphoma Using a Multiplexed Targeted Sequencing Assay.
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Drieux F, Ruminy P, Sater V, Marchand V, Fataccioli V, Lanic MD, Viennot M, Viailly PJ, Sako N, Robe C, Dupuy A, Vallois D, Veresezan L, Poullot E, Picquenot JM, Bossard C, Parrens M, Lemonnier F, Jardin F, de Leval L, and Gaulard P
- Subjects
- Biomarkers, Tumor, Chromosome Banding, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Reproducibility of Results, Sensitivity and Specificity, Gene Fusion, Gene Rearrangement, High-Throughput Nucleotide Sequencing methods, Lymphoma, T-Cell, Peripheral diagnosis, Lymphoma, T-Cell, Peripheral genetics, Multiplex Polymerase Chain Reaction methods, Oncogene Proteins, Fusion
- Abstract
The genetic basis of peripheral T-cell lymphoma (PTCL) is complex and encompasses several recurrent fusion transcripts discovered over the past years by means of massive parallel sequencing. However, there is currently no affordable and rapid technology for their simultaneous detection in clinical samples. Herein, we developed a multiplex ligation-dependent RT-PCR-based assay, followed by high-throughput sequencing, to detect 33 known PTCL-associated fusion transcripts. Anaplastic lymphoma kinase (ALK) fusion transcripts were detected in 15 of 16 ALK-positive anaplastic large-cell lymphomas. The latter case was further characterized by a novel SATB1_ALK fusion transcript. Among 239 other PTCLs, representative of nine entities, non-ALK fusion transcripts were detected in 24 samples, mostly of follicular helper T-cell (TFH) derivation. The most frequent non-ALK fusion transcript was ICOS_CD28 in nine TFH-PTCLs, one PTCL not otherwise specified, and one adult T-cell leukemia/lymphoma, followed by VAV1 rearrangements with multiple partners (STAP2, THAP4, MYO1F, and CD28) in five samples (three PTCL not otherwise specified and two TFH-PTCLs). The other rearrangements were CTLA4_CD28 (one TFH-PTCL), ITK_SYK (two TFH-PTCLs), ITK_FER (one TFH-PTCL), IKZF2_ERBB4 (one TFH-PTCL and one adult T-cell leukemia/lymphoma), and TP63_TBL1XR1 (one ALK-negative anaplastic large-cell lymphoma). All fusions detected by our assay were validated by conventional RT-PCR and Sanger sequencing in 30 samples with adequate material. The simplicity and robustness of this targeted multiplex assay make it an attractive tool for the characterization of these heterogeneous diseases., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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23. Integrative analysis of a phase 2 trial combining lenalidomide with CHOP in angioimmunoblastic T-cell lymphoma.
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Lemonnier F, Safar V, Beldi-Ferchiou A, Cottereau AS, Bachy E, Cartron G, Fataccioli V, Pelletier L, Robe C, Letourneau A, Missiaglia E, Fourati S, Moles-Moreau MP, Delmer A, Bouabdallah R, Voillat L, Becker S, Bossard C, Parrens M, Casasnovas O, Cacheux V, Régny C, Camus V, Delfau-Larue MH, Meignan M, de Leval L, Gaulard P, and Haioun C
- Subjects
- Aged, Aged, 80 and over, Humans, Lenalidomide, Middle Aged, Prospective Studies, Rituximab, Antineoplastic Combined Chemotherapy Protocols adverse effects, Lymphoma, T-Cell
- Abstract
Angioimmunoblastic T-cell lymphoma (AITL) is a frequent T-cell lymphoma in the elderly population that has a poor prognosis when treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy. Lenalidomide, which has been safely combined with CHOP to treat B-cell lymphoma, has shown efficacy as a single agent in AITL treatment. We performed a multicentric phase 2 trial combining 25 mg lenalidomide daily for 14 days per cycle with 8 cycles of CHOP21 in previously untreated AITL patients aged 60 to 80 years. The primary objective was the complete metabolic response (CMR) rate at the end of treatment. Seventy-eight of the 80 patients enrolled were included in the efficacy and safety analysis. CMR was achieved in 32 (41%; 95% confidence interval [CI], 30%-52.7%) patients, which was below the prespecified CMR rate of 55% defined as success in the study. The 2-year progression-free survival (PFS) was 42.1% (95% CI, 30.9%-52.8%), and the 2-year overall survival was 59.2% (95% CI, 47.3%-69.3%). The most common toxicities were hematologic and led to treatment discontinuation in 15% of patients. This large prospective and uniform series of AITL treatment data was used to perform an integrative analysis of clinical, pathologic, biologic, and molecular data. TET2, RHOA, DNMT3A, and IDH2 mutations were present in 78%, 54%, 32%, and 22% of patients, respectively. IDH2 mutations were associated with distinct pathologic and clinical features and DNMT3A was associated with shorter PFS. In conclusion, the combination of lenalidomide and CHOP did not improve the CMR in AITL patients. This trial clarified the clinical impact of recurrent mutations in AITL. This trial was registered at www.clincialtrials.gov as #NCT01553786., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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24. Defining signatures of peripheral T-cell lymphoma with a targeted 20-marker gene expression profiling assay.
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Drieux F, Ruminy P, Abdel-Sater A, Lemonnier F, Viailly PJ, Fataccioli V, Marchand V, Bisig B, Letourneau A, Parrens M, Bossard C, Bruneau J, Dobay P, Veresezan L, Dupuy A, Pujals A, Robe C, Sako N, Copie-Bergman C, Delfau-Larue MH, Picquenot JM, Tilly H, Delarue R, Jardin F, de Leval L, and Gaulard P
- Subjects
- Adult, Gene Expression Profiling, Herpesvirus 4, Human, Humans, Reproducibility of Results, Epstein-Barr Virus Infections, Lymphoma, T-Cell, Peripheral diagnosis, Lymphoma, T-Cell, Peripheral genetics
- Abstract
Peripheral T-cell lymphoma comprises a heterogeneous group of mature non-Hodgkin lymphomas. Their diagnosis is challenging, with up to 30% of cases remaining unclassifiable and referred to as "not otherwise specified". We developed a reverse transcriptase-multiplex ligation-dependent probe amplification gene expression profiling assay to differentiate the main T-cell lymphoma entities and to study the heterogeneity of the "not specified" category. The test evaluates the expression of 20 genes, including 17 markers relevant to T-cell immunology and lymphoma biopathology, one Epstein-Barr virus-related transcript, and variants of RHOA (G17V) and IDH2 (R172K/T). By unsupervised hierarchical clustering, our assay accurately identified 21 of 21 ALK-positive anaplastic large cell lymphomas, 16 of 16 extranodal natural killer (NK)/T-cell lymphomas, 6 of 6 hepatosplenic T-cell lymphomas, and 13 of 13 adult T-cell leukemia/lymphomas. ALK-negative anaplastic lymphomas (n=34) segregated into one cytotoxic cluster (n=10) and one non-cytotoxic cluster expressing Th2 markers (n=24) and enriched in DUSP22 -rearranged cases. The 63 T
FH -derived lymphomas divided into two subgroups according to a predominant TFH (n=50) or an enrichment in Th2 (n=13) signatures. We next developed a support vector machine predictor which attributed a molecular class to 27 of 77 not specified T-cell lymphomas: 17 TFH , five cytotoxic ALK-negative anaplastic and five NK/T-cell lymphomas. Among the remaining cases, we identified two cell-of-origin subgroups corresponding to cytotoxic/Th1 (n=19) and Th2 (n=24) signatures. A reproducibility test on 40 cases yielded a 90% concordance between three independent laboratories. This study demonstrates the applicability of a simple gene expression assay for the classification of peripheral T-cell lymphomas. Its applicability to routinely-fixed samples makes it an attractive adjunct in diagnostic practice., (Copyright© 2020 Ferrata Storti Foundation.)- Published
- 2020
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25. Gene alterations in epigenetic modifiers and JAK-STAT signaling are frequent in breast implant-associated ALCL.
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Laurent C, Nicolae A, Laurent C, Le Bras F, Haioun C, Fataccioli V, Amara N, Adélaïde J, Guille A, Schiano JM, Tesson B, Traverse-Glehen A, Chenard MP, Mescam L, Moreau A, Chassagne-Clement C, Somja J, Escudié F, André M, Martin N, Lacroix L, Lemonnier F, Hamy AS, Reyal F, Bannier M, Oberic L, Prade N, Frénois FX, Beldi-Ferchiou A, Delfau-Larue MH, Bouabdallah R, Birnbaum D, Brousset P, Xerri L, and Gaulard P
- Subjects
- Adult, Aged, Aged, 80 and over, DNA Copy Number Variations, Female, Genome, Human, Humans, Lymphoma, Large-Cell, Anaplastic pathology, Middle Aged, Mutation genetics, Breast Implants adverse effects, Epigenesis, Genetic, Janus Kinases metabolism, Lymphoma, Large-Cell, Anaplastic etiology, Lymphoma, Large-Cell, Anaplastic genetics, STAT Transcription Factors metabolism, Signal Transduction
- Abstract
The oncogenic events involved in breast implant-associated anaplastic large cell lymphoma (BI-ALCL) remain elusive. To clarify this point, we have characterized the genomic landscape of 34 BI-ALCLs (15 tumor and 19 in situ subtypes) collected from 54 BI-ALCL patients diagnosed through the French Lymphopath network. Whole-exome sequencing (n = 22, with paired tumor/germline DNA) and/or targeted deep sequencing (n = 24) showed recurrent mutations of epigenetic modifiers in 74% of cases, involving notably KMT2C (26%), KMT2D (9%), CHD2 (15%), and CREBBP (15%). KMT2D and KMT2C mutations correlated with a loss of H3K4 mono- and trimethylation by immunohistochemistry. Twenty cases (59%) showed mutations in ≥1 member of the JAK/STAT pathway, including STAT3 (38%), JAK1 (18%), and STAT5B (3%), and in negative regulators, including SOCS3 (6%), SOCS1 (3%), and PTPN1 (3%). These mutations were more frequent in tumor-type samples than in situ samples (P = .038). All BI-ALCLs expressed pSTAT3, regardless of the mutational status of genes in the JAK/STAT pathway. Mutations in the EOMES gene (12%) involved in lymphocyte development, PI3K-AKT/mTOR (6%), and loss-of-function mutations in TP53 (12%) were also identified. Copy-number aberration (CNA) analysis identified recurrent alterations, including gains on chromosomes 2, 9p, 12p, and 21 and losses on 4q, 8p, 15, 16, and 20. Regions of CNA encompassed genes involved in the JAK/STAT pathway and epigenetic regulators. Our results show that the BI-ALCL genomic landscape is characterized by not only JAK/STAT activating mutations but also loss-of-function alterations of epigenetic modifiers., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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26. Clinical spectrum, evolution, and management of autoimmune cytopenias associated with angioimmunoblastic T-cell lymphoma.
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Crickx E, Poullot E, Moulis G, Goulabchand R, Fieschi C, Galicier L, Meignin V, Coppo P, Delarue R, Casasnovas O, Roos-Weil D, de Leval L, Parrens M, Michel M, Dupuis J, Le Bras F, Fataccioli V, Martin-Garcia N, Godeau B, Haïoun C, Gaulard P, and Mahévas M
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Autoimmune Diseases diagnosis, Biopsy, Disease Management, Disease Susceptibility, Female, Humans, Immunoblastic Lymphadenopathy etiology, Immunoblastic Lymphadenopathy mortality, Immunoglobulins, Intravenous therapeutic use, Lymphoma, T-Cell etiology, Lymphoma, T-Cell mortality, Male, Middle Aged, Neoplasm Staging, Pancytopenia diagnosis, Phenotype, Retrospective Studies, Symptom Assessment, Treatment Outcome, Autoimmune Diseases complications, Immunoblastic Lymphadenopathy diagnosis, Immunoblastic Lymphadenopathy therapy, Lymphoma, T-Cell diagnosis, Lymphoma, T-Cell therapy, Pancytopenia complications
- Abstract
Objective: Angioimmunoblastic T-cell lymphoma (AITL) is frequently associated with autoimmune cytopenia (AIC). Whether such patients have a particular phenotype and require particular management is unclear., Method: Angioimmunoblastic T-cell lymphoma patients from the multicentric database of the Lymphoma Study Association presenting with AIC during disease course were included and matched to AITL patients without AIC (1/5 ratio)., Results: At diagnosis, AIC patients (n = 28) had more spleen and bone marrow involvement (54% vs 19% and 71% vs 34%, P < 0.001), Epstein-Barr virus replication (89% vs 39%, P < 0.001), gamma globulin titers (median 23 vs 15 g/L, P = 0.002), and proliferating B cells and plasmablasts in biopsies, as compared to control patients (n = 136). The 28 AIC patients had 41 episodes of AIC, diagnosed concomitantly with AITL in 23 (82%) cases. After a median follow-up of 24 months (range 3-155), 10 patients relapsed, all associated with AITL relapse., Conclusion: Our results provide new insight into AIC associated with AITL by highlighting the significant interplay between AITL and B-cell activation leading to subsequent autoimmunity., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2019
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27. DNA methylation profiling of hepatosplenic T-cell lymphoma.
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Bergmann AK, Fataccioli V, Castellano G, Martin-Garcia N, Pelletier L, Ammerpohl O, Bergmann J, Bhat J, Pau ECS, Martín-Subero JI, Moffitt AB, Valencia A, Oberg HH, Wesch D, Jayne S, Dyer MJS, Kabelitz D, Gaulard P, and Siebert R
- Subjects
- Biomarkers, Tumor, Epigenesis, Genetic, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Immunohistochemistry, DNA Methylation, Lymphoma, T-Cell diagnosis, Lymphoma, T-Cell genetics, Transcriptome
- Published
- 2019
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28. Treatment with 5-azacytidine induces a sustained response in patients with angioimmunoblastic T-cell lymphoma.
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Lemonnier F, Dupuis J, Sujobert P, Tournillhac O, Cheminant M, Sarkozy C, Pelletier L, Marçais A, Robe C, Fataccioli V, Haioun C, Hermine O, Gaulard P, and Delarue R
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Lymphoma, T-Cell pathology, Male, Middle Aged, Retrospective Studies, Treatment Outcome, Antimetabolites, Antineoplastic therapeutic use, Azacitidine therapeutic use, Lymphoma, T-Cell drug therapy
- Published
- 2018
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29. Multiple Ways to Detect IDH2 Mutations in Angioimmunoblastic T-Cell Lymphoma from Immunohistochemistry to Next-Generation Sequencing.
- Author
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Dupuy A, Lemonnier F, Fataccioli V, Martin-Garcia N, Robe C, Pelletier R, Poullot E, Moktefi A, Mokhtari K, Rousselet MC, Traverse-Glehen A, Delarue R, Tournilhac O, Delfau-Larue MH, Haioun C, Ortonne N, Copie-Bergman C, de Leval L, Pujals A, and Gaulard P
- Subjects
- Amino Acid Substitution genetics, Base Sequence, Codon genetics, DNA Mutational Analysis, Humans, Immunohistochemistry, Isocitrate Dehydrogenase genetics, Sensitivity and Specificity, High-Throughput Nucleotide Sequencing methods, Immunoblastic Lymphadenopathy genetics, Immunoblastic Lymphadenopathy pathology, Lymphoma, T-Cell genetics, Lymphoma, T-Cell pathology, Mutation genetics
- Abstract
Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma associated with chemoresistance and a poor prognosis. Various nonsynonymous mutations in the R172 residue of IDH2 are present in 20% to 30% of AITL patients. In addition to their diagnostic value, these mutations are potentially targetable, especially by isocitrate dehydrogenase (IDH) 2 inhibitor, and therefore their identification in a routine setting is clinically relevant. However, in AITL, the neoplastic cells may be scarce, making the identification of molecular anomalies difficult. We evaluated the diagnostic value of different methods to detect IDH2 mutations in formalin-fixed, paraffin-embedded tumor samples. Immunohistochemistry with an anti-IDH2 R172K antibody, Sanger sequencing, high-resolution melting PCR, allele-specific real-time quantitative PCR, and next-generation sequencing (NGS) were applied to biopsy specimens from 42 AITL patients. We demonstrate that the IDH2 R172K antibody is specific to this amino acid substitution and highly sensitive for the detection of the IDH2
R172K variant, the most frequent substitution in this disease. In our study, NGS and allele-specific real-time quantitative PCR displayed a good sensitivity, detecting 96% and 92% of IDH2 mutations, respectively, in contrast to Sanger sequencing and high-resolution melting PCR, which showed a significantly lower detection rate (58% and 42%, respectively). These results suggest that a combination of immunohistochemistry and AS-PCR or NGS should be considered for the identification of IDH2 mutations in AITL in a routine setting., (Copyright © 2018 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
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30. RNA fusions involving CD28 are rare in peripheral T-cell lymphomas and concentrate mainly in those derived from follicular helper T cells.
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Vallois D, Dupuy A, Lemonnier F, Allen G, Missiaglia E, Fataccioli V, Ortonne N, Clavert A, Delarue R, Rousselet MC, Fabiani B, Llamas-Gutierrez F, Ogawa S, Thome M, Ko YH, Kataoka K, Gaulard P, and de Leval L
- Subjects
- CTLA-4 Antigen genetics, Gene Fusion, Humans, Inducible T-Cell Co-Stimulator Protein genetics, CD28 Antigens genetics, Lymphoma, T-Cell, Peripheral genetics, RNA genetics, T-Lymphocytes, Helper-Inducer chemistry
- Published
- 2018
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31. Loss of 5-hydroxymethylcytosine is a frequent event in peripheral T-cell lymphomas.
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Lemonnier F, Poullot E, Dupuy A, Couronné L, Martin N, Scourzic L, Fataccioli V, Bruneau J, Cairns RA, Mak TW, Bernard OA, de Leval L, and Gaulard P
- Subjects
- 5-Methylcytosine analysis, 5-Methylcytosine metabolism, Epigenesis, Genetic genetics, Humans, Lymphoma, T-Cell, Peripheral metabolism, Methylation, 5-Methylcytosine analogs & derivatives, Lymphoma, T-Cell, Peripheral genetics
- Published
- 2018
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32. Integrative clinicopathological and molecular analyses of angioimmunoblastic T-cell lymphoma and other nodal lymphomas of follicular helper T-cell origin.
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Dobay MP, Lemonnier F, Missiaglia E, Bastard C, Vallois D, Jais JP, Scourzic L, Dupuy A, Fataccioli V, Pujals A, Parrens M, Le Bras F, Rousset T, Picquenot JM, Martin N, Haioun C, Delarue R, Bernard OA, Delorenzi M, de Leval L, and Gaulard P
- Subjects
- Aged, DNA (Cytosine-5-)-Methyltransferases genetics, DNA (Cytosine-5-)-Methyltransferases metabolism, DNA Methyltransferase 3A, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Dendritic Cells metabolism, Dendritic Cells pathology, Diagnosis, Differential, Dioxygenases, Eosinophils metabolism, Eosinophils pathology, Female, Humans, Immunoblastic Lymphadenopathy genetics, Immunoblastic Lymphadenopathy mortality, Immunoblastic Lymphadenopathy pathology, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase metabolism, Lymphoma, Follicular genetics, Lymphoma, Follicular mortality, Lymphoma, Follicular pathology, Lymphoma, T-Cell, Peripheral genetics, Lymphoma, T-Cell, Peripheral mortality, Lymphoma, T-Cell, Peripheral pathology, Male, Middle Aged, Mutation, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Survival Analysis, T-Lymphocytes, Helper-Inducer metabolism, Terminology as Topic, rhoA GTP-Binding Protein genetics, rhoA GTP-Binding Protein metabolism, Gene Expression Regulation, Neoplastic, Immunoblastic Lymphadenopathy diagnosis, Lymphoma, Follicular diagnosis, Lymphoma, T-Cell, Peripheral diagnosis, T-Lymphocytes, Helper-Inducer pathology
- Published
- 2017
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33. The Genetic Basis of Hepatosplenic T-cell Lymphoma.
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McKinney M, Moffitt AB, Gaulard P, Travert M, De Leval L, Nicolae A, Raffeld M, Jaffe ES, Pittaluga S, Xi L, Heavican T, Iqbal J, Belhadj K, Delfau-Larue MH, Fataccioli V, Czader MB, Lossos IS, Chapman-Fredricks JR, Richards KL, Fedoriw Y, Ondrejka SL, Hsi ED, Low L, Weisenburger D, Chan WC, Mehta-Shah N, Horwitz S, Bernal-Mizrachi L, Flowers CR, Beaven AW, Parihar M, Baseggio L, Parrens M, Moreau A, Sujobert P, Pilichowska M, Evens AM, Chadburn A, Au-Yeung RK, Srivastava G, Choi WW, Goodlad JR, Aurer I, Basic-Kinda S, Gascoyne RD, Davis NS, Li G, Zhang J, Rajagopalan D, Reddy A, Love C, Levy S, Zhuang Y, Datta J, Dunson DB, and Davé SS
- Subjects
- ATPases Associated with Diverse Cellular Activities, Adolescent, Adult, Aged, Base Sequence, Child, Child, Preschool, DNA-Binding Proteins, Enhancer of Zeste Homolog 2 Protein, Exome genetics, Female, Humans, Liver Neoplasms complications, Liver Neoplasms pathology, Lymphoma, T-Cell complications, Lymphoma, T-Cell pathology, Male, Middle Aged, Proto-Oncogene Proteins p21(ras), Splenic Neoplasms complications, Splenic Neoplasms pathology, Transcription Factors, Tumor Suppressor Proteins genetics, Young Adult, DNA Helicases genetics, Histone-Lysine N-Methyltransferase genetics, Liver Neoplasms genetics, Lymphoma, T-Cell genetics, Splenic Neoplasms genetics, Tumor Suppressor Protein p53 genetics
- Abstract
Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including SETD2, INO80 , and ARID1B , were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS , and TP53 SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets. Significance: We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines SETD2 as a tumor suppressor gene in HSTL and implicates genes including INO80 and PIK3CD in the disease. Cancer Discov; 7(4); 369-79. ©2017 AACR. See related commentary by Yoshida and Weinstock, p. 352 This article is highlighted in the In This Issue feature, p. 339 ., (©2017 American Association for Cancer Research.)
- Published
- 2017
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34. The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development.
- Author
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Lemonnier F, Cairns RA, Inoue S, Li WY, Dupuy A, Broutin S, Martin N, Fataccioli V, Pelletier R, Wakeham A, Snow BE, de Leval L, Pujals A, Haioun C, Paci A, Tobin ER, Narayanaswamy R, Yen K, Jin S, Gaulard P, and Mak TW
- Subjects
- Animals, Biomarkers, Tumor, Flow Cytometry, Gene Expression Regulation, Neoplastic, Genotype, Humans, Isocitrate Dehydrogenase metabolism, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Lymphocytes metabolism, Lymphoma, T-Cell metabolism, Mice, Mice, Knockout, Mutation, Glutarates metabolism, Isocitrate Dehydrogenase genetics, Lymphoma, T-Cell immunology
- Abstract
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., Competing Interests: The authors declare no conflict of interest.
- Published
- 2016
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35. Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas.
- Author
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Vallois D, Dobay MP, Morin RD, Lemonnier F, Missiaglia E, Juilland M, Iwaszkiewicz J, Fataccioli V, Bisig B, Roberti A, Grewal J, Bruneau J, Fabiani B, Martin A, Bonnet C, Michielin O, Jais JP, Figeac M, Bernard OA, Delorenzi M, Haioun C, Tournilhac O, Thome M, Gascoyne RD, Gaulard P, and de Leval L
- Subjects
- Biomarkers, Tumor genetics, Cohort Studies, Follow-Up Studies, High-Throughput Nucleotide Sequencing methods, Humans, Immunoblastic Lymphadenopathy immunology, Immunoblastic Lymphadenopathy pathology, Lymphoma, Follicular immunology, Lymphoma, Follicular pathology, Lymphoma, T-Cell, Peripheral immunology, Lymphoma, T-Cell, Peripheral pathology, Neoplasm Staging, Prognosis, Genes, T-Cell Receptor genetics, Immunoblastic Lymphadenopathy genetics, Lymphoma, Follicular genetics, Lymphoma, T-Cell, Peripheral genetics, Mutation genetics, Signal Transduction, T-Lymphocytes, Helper-Inducer immunology, rhoA GTP-Binding Protein genetics
- Abstract
Angioimmunoblastic T-cell lymphoma (AITL) and other lymphomas derived from follicular T-helper cells (TFH) represent a large proportion of peripheral T-cell lymphomas (PTCLs) with poorly understood pathogenesis and unfavorable treatment results. We investigated a series of 85 patients with AITL (n = 72) or other TFH-derived PTCL (n = 13) by targeted deep sequencing of a gene panel enriched in T-cell receptor (TCR) signaling elements. RHOA mutations were identified in 51 of 85 cases (60%) consisting of the highly recurrent dominant negative G17V variant in most cases and a novel K18N in 3 cases, the latter showing activating properties in in vitro assays. Moreover, half of the patients carried virtually mutually exclusive mutations in other TCR-related genes, most frequently in PLCG1 (14.1%), CD28 (9.4%, exclusively in AITL), PI3K elements (7%), CTNNB1 (6%), and GTF2I (6%). Using in vitro assays in transfected cells, we demonstrated that 9 of 10 PLCG1 and 3 of 3 CARD11 variants induced MALT1 protease activity and increased transcription from NFAT or NF-κB response element reporters, respectively. Collectively, the vast majority of variants in TCR-related genes could be classified as gain-of-function. Accordingly, the samples with mutations in TCR-related genes other than RHOA had transcriptomic profiles enriched in signatures reflecting higher T-cell activation. Although no correlation with presenting clinical features nor significant impact on survival was observed, the presence of TCR-related mutations correlated with early disease progression. Thus, targeting of TCR-related events may hold promise for the treatment of TFH-derived lymphomas., (© 2016 by The American Society of Hematology.)
- Published
- 2016
- Full Text
- View/download PDF
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