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1. HOX11L2/TLX3 is transcriptionally activated through T-cell regulatory elements downstream of BCL11B as a result of the t(5;14)(q35;q32)

Author

Virginie Penard-Lacronique, Isabelle André-Schmutz, Xin-Ying Su, Roland Berger, Paola Ballerini, Claudie Lemercier, Véronique Della-Valle, Francine Mugneret, Serge Romana, Michel Lessard, Isabelle Radford-Weiss, Marina Lafage-Pochitaloff, Olivier Bernard, Génétique des hémopathies humaines ( EMI 210 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Developpement Normal et Pathologique du Système Immunitaire, Contrôle moléculaire de la réponse immune specifique, Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Cytogénétique, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Service d'Hématologie Biologique, Assistance publique - Hôpitaux de Paris (AP-HP), Laboratoire d'Hématologie, CHU Strasbourg, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Génétique des hémopathies humaines (EMI 210), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)

Subjects
Oncogene Proteins, Fusion, Transcription, Genetic, T-Lymphocytes, BCL11B, Chromosomal translocation, MESH : Promoter Regions, Genetic, MESH : Oncogene Proteins, Fusion, Biochemistry, Jurkat cells, Translocation, Genetic, Jurkat Cells, MESH : Chromosomes, Human, Pair 5, 0302 clinical medicine, MESH : Translocation, Genetic, Transcription (biology), MESH: Jurkat Cells, Leukemia-Lymphoma, Adult T-Cell, MESH: Leukemia-Lymphoma, Adult T-Cell, MESH : Homeodomain Proteins, Promoter Regions, Genetic, MESH : Jurkat Cells, Oncogene Proteins, 0303 health sciences, MESH : Chromosomes, Human, Pair 14, MESH : Oncogene Proteins, MESH : Tumor Suppressor Proteins, Cell Differentiation, Hematology, Transfection, MESH: Translocation, Genetic, DNA-Binding Proteins, medicine.anatomical_structure, MESH: Repressor Proteins, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 5, MESH : DNA-Binding Proteins, MESH : Repressor Proteins, MESH : Cell Differentiation, MESH: Cell Differentiation, MESH: Chromosomes, Human, Pair 5, T cell, Immunology, Biology, 03 medical and health sciences, MESH: Oncogene Proteins, MESH: Promoter Regions, Genetic, MESH: Homeodomain Proteins, medicine, Humans, MESH: Tumor Suppressor Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Chromosomes, Human, Pair 14, Homeodomain Proteins, MESH : T-Lymphocytes, MESH: Humans, Recombinase activity, Tumor Suppressor Proteins, MESH: Transcription, Genetic, MESH : Humans, MESH : Transcription, Genetic, Cell Biology, T lymphocyte, Molecular biology, MESH : Leukemia-Lymphoma, Adult T-Cell, Repressor Proteins, MESH: T-Lymphocytes, MESH: Chromosomes, Human, Pair 14, MESH: DNA-Binding Proteins, MESH: Oncogene Proteins, Fusion
Abstract

International audience; The t(5;14)(q35;q32) chromosomal translocation is specifically observed in up to 20% of childhood T-cell acute lymphoblastic leukemia (T-ALL). It affects the BCL11B/CTIP2 locus on chromosome 14 and the RANBP17-TLX3/HOX11L2 region on chromosome 5. It leads to ectopic activation of TLX3/HOX11L2. To investigate the reasons of the association between t(5;14) and T-ALL, we isolated the translocation breakpoints in 8 t(5;14) patients. Sequence analyses did not involve recombinase activity in the genesis of the translocation. We used DNAse1 hypersensitive experiments to locate transcriptional regulatory elements downstream of BCL11B. By transient transfection experiments, 2 of the 6 regions demonstrated cis-activation properties in T cells and were also effective on the TLX3 promoter. Our data indicate that the basis of the specific association between t(5;14) and T-ALL lies on the juxtaposition of TLX3 to long-range cis-activating regions active during T-cell differentiation.

Published
2006
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2. Pediatric-inspired intensified therapy of adult T-ALL reveals the favorable outcome of NOTCH1/FBXW7 mutations, but not of low ERG/BAALC expression: a GRAALL study

Author

Ben Abdelali, Raouf, Asnafi, Vahid, Leguay, Thibaut, Boissel, Nicolas, Buzyn, Agnès, Chevallier, Patrice, Thomas, Xavier, Lepretre, Stephane, Huguet, Françoise, Vey, Norbert, Escoffre-Barbe, Martine, Tavernier, Emmanuelle, Reman, Oumedaly, Fegueux, Nathalie, Turlure, Pascal, Rousselot, Philippe, Cahn, Jean-Yves, Lheritier, Veronique, Chalandon, Yves, Béné, Marie-Christine, Macintyre, Elizabeth, Dombret, Hervé, Ifrah, Norbert, Renseigné, Non, Université Paris Descartes - Paris 5 (UPD5), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), equipe 14, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), 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), Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Hematology (IPC-Marseille), Service d'hématologie clinique, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Service d'hématologie et oncologie médicale, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Hematology, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Service d'Immunologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Lymphocyte et cancer, IFR105-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie clinique [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Avicenne [AP-HP], Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Edouard Herriot [CHU - HCL], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Hôpital Lapeyronie-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Université Paris Descartes - Paris 5 ( UPD5 ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), 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 ), Université Toulouse III - Paul Sabatier ( UPS ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou, Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Lapeyronie, Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble, Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], IFR105-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne, Cytokines, hématopoïèse et réponse immune (CHRI), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Rennes (UR)-Hôpital Pontchaillou, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Centre de Recherche en Cancérologie de Lyon (CRCL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Avicenne, and Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)

Subjects
Oncology, Male, MESH : F-Box Proteins, MESH : Prospective Studies, Cell Cycle Proteins, MESH: Receptor, Notch1, Biochemistry, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, MESH : Cell Cycle Proteins, Neoplasm Proteins/genetics, MESH : Child, Clinical Protocols, MESH: Child, Mutational status, Favorable outcome, Prospective Studies, MESH: Leukemia-Lymphoma, Adult T-Cell, Receptor, Notch1, Child, ComputingMilieux_MISCELLANEOUS, MESH: Treatment Outcome, ddc:616, 0303 health sciences, Mutation, MESH : Trans-Activators, MESH: Middle Aged, Prognosis, Neoplasm Proteins, MESH: Young Adult, 030220 oncology & carcinogenesis, F-Box Proteins/genetics, Erg, medicine.medical_specialty, MESH: Gene Expression, Immunology, MESH : Young Adult, Disease-Free Survival, MESH: Prognosis, 03 medical and health sciences, MESH : Neoplasm Proteins, MESH: Cell Cycle Proteins, MESH : Adolescent, Humans, MESH : Middle Aged, Ubiquitin-Protein Ligases/genetics, MESH : Predictive Value of Tests, MESH : Clinical Protocols, MESH: Kaplan-Meier Estimate, Cell Cycle Proteins/genetics, MESH: Adolescent, Receptor, Notch1/genetics, MESH: Humans, F-Box Proteins, MESH : Humans, MESH: Adult, Leukemia-Lymphoma, Adult T-Cell/classification/drug therapy/genetics, MESH: Ubiquitin-Protein Ligases, MESH : Leukemia-Lymphoma, Adult T-Cell, MESH : Gene Expression, MESH: Disease-Free Survival, Adult Acute Lymphoblastic Leukemia, MESH : Ubiquitin-Protein Ligases, Carcinogenesis, MESH: Female, MESH: Neoplasm Proteins, Multivariate analysis, F-Box-WD Repeat-Containing Protein 7, Gene Expression, Kaplan-Meier Estimate, medicine.disease_cause, Bioinformatics, MESH: Clinical Protocols, Leukemia-Lymphoma, Adult T-Cell, MESH : Female, BAALC, MESH : Prognosis, MESH : Receptor, Notch1, Hematology, MESH : Adult, Middle Aged, MESH: Predictive Value of Tests, Treatment Outcome, MESH : Disease-Free Survival, Female, MESH : Mutation, Adult, MESH: Mutation, Adolescent, MESH: Trans-Activators, MESH : Male, Ubiquitin-Protein Ligases, MESH: F-Box Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : Treatment Outcome, Trans-Activators/genetics, MESH : Kaplan-Meier Estimate, Young Adult, Transcriptional Regulator ERG, Predictive Value of Tests, Internal medicine, medicine, 030304 developmental biology, business.industry, Cell Biology, MESH: Male, MESH: Prospective Studies, Trans-Activators, business
Abstract

Despite recent progress in the understanding of acute lymphoblastic leukemia (T-ALL) oncogenesis, few markers are sufficiently frequent in large subgroups to allow their use in therapeutic stratification. Low ERG and BAALC expression (E/Blow) and NOTCH1/FBXW7 (N/F) mutations have been proposed as powerful prognostic markers in large cohorts of adult T-ALL. We therefore compared the predictive prognostic value of N/F mutations versus E/Blow in 232 adult T-ALLs enrolled in the LALA-94 and Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocols. The outcome of T-ALLs treated in the pediatric-inspired GRAALL trials was significantly superior to the LALA-94 trial. Overall, 43% and 69% of adult T-ALL patients were classified as E/Blow and N/F mutated, respectively. Strikingly, the good prognosis of N/F mutated patients was stronger in more intensively treated, pediatric-inspired GRAALL patients. The E/B expression level did not influence the prognosis in any subgroup. N/F mutation status and the GRAALL trial were the only 2 independent factors that correlated with longer overall survival by multivariate analysis. This study demonstrates that the N/F mutational status and treatment protocol are major outcome determinants for adults with T-ALL, the benefit of pediatric inspired protocols being essentially restricted to the N/F mutated subgroup.

Published
2011
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3. Impact of genotype on survival of children with T-cell acute lymphoblastic leukemia treated according to the French protocol FRALLE-93: the effect of TLX3/HOX11L2 gene expression on outcome

Author

André Baruchel, Yves Perel, Anne Hagemejier, Guy Leverger, Judith Landman-Parker, Paola Ballerini, Virginie Gandemer, François Sigaux, Gérard Michel, Claudine Schmitt, Vahid Asnafi, Jean Michel Cayuela, Sylvie Fasola, Marie Françoise Auclerc, Luc Douay, Thierry Leblanc, Myriam Labopin, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'hématologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'hématologie, Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], CEREST-TC [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d'onco-hématologie pédiatrique, hôpital Sud, Service d'hématologie pédiatrique et oncologie, CHU Bordeaux [Bordeaux]-Hôpital Pellegrin, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'hématologie, Service d'oncologie et hématologie, Hôpital d'enfants, Department of Human Genetics, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), supported by Chugai France (Dr. Thierry Guillot) and SFCE (Société Française des Cancers de l'Enfant)., Service d'hématologie-immunologie-oncologie pédiatrique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], CHU Saint-Antoine [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Hôpital Sud, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Catholic University of Leuven ( KU Leuven ), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), and De Villemeur, Hervé

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Male, Oncology, Time Factors, Transcription, Genetic, MESH : Genotype, MESH : Child, Preschool, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Genotype, 0302 clinical medicine, MESH : Child, hemic and lymphatic diseases, MESH: Child, Gene expression, Genotype, MESH : Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia-Lymphoma, Adult T-Cell, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, Medicine, MESH : Female, MESH : Homeodomain Proteins, MESH: Leukemia-Lymphoma, Adult T-Cell, Child, Regulation of gene expression, 0303 health sciences, MESH : Prognosis, Hematology, Hazard ratio, MESH : Infant, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, MESH: Follow-Up Studies, MESH: Gene Expression Regulation, Neoplastic, Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH : Adult, Prognosis, MESH : Survival Rate, MESH: Infant, 3. Good health, Gene Expression Regulation, Neoplastic, Survival Rate, NUP214-ABL1, Child, Preschool, 030220 oncology & carcinogenesis, outcome, Female, France, TLX3/HOX11L2, MESH : Time Factors, Adult, medicine.medical_specialty, Adolescent, MESH: Survival Rate, MESH : Gene Expression Regulation, Neoplastic, MESH : Male, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Prognosis, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH : Adolescent, Internal medicine, MESH: Homeodomain Proteins, Humans, MESH : France, Survival rate, 030304 developmental biology, Homeodomain Proteins, MESH: Adolescent, MESH: Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH: Humans, business.industry, MESH: Transcription, Genetic, MESH : Humans, MESH: Time Factors, MESH: Child, Preschool, Infant, MESH : Transcription, Genetic, childhood T-cell acute lymphoblastic leukemia, MESH : Follow-Up Studies, MESH: Adult, MESH : Leukemia-Lymphoma, Adult T-Cell, MESH: Male, MESH: France, El Niño, Fusion transcript, Immunology, SIL-TAL1, business, MESH: Female, Follow-Up Studies
Abstract

International audience; BACKGROUND: The prognostic value of the ectopic activation of TLX3 gene expression, a major oncogenetic event associated with pediatric T-cell acute lymphoblastic leukemia, is controversial. Likewise, the frequency and the prognostic significance in pediatric T-cell acute lymphoblastic leukemia of the newly characterized NUP214-ABL1 fusion transcript is not yet clear. DESIGN AND METHODS: Two hundred children with T-cell acute lymphoblastic leukemia were treated in the French FRALLE-93 study from 1993 to 1999. The expression of TLX3, TLX1 and SILTAL1 genes was analyzed in samples from 92 patients by real-time quantitative reverse transcriptase polymerase chain reaction. Most of these samples were further studied for NUP214-ABL1 and CALM-AF10 fusion transcripts. RESULTS: The median follow-up was 7.9 years. At 5 years the overall survival (+/- standard deviation, %) was 62 (+/-3%) and leukemia-free survival was 58 (+/-3%). Patients with T-cell acute lymphoblastic leukemia positive for TLX3 had a poorer survival compared to those with T-ALL negative for TLX3 (overall survival: 45+/-11% vs. 57+/-5%, p=0.049). In multivariate analysis, TLX3 expression was an independent adverse risk factor predicting relapse with a hazard ratio of 2.44 (p=0.017) and an overall survival with a hazard ratio of 3.7 (p=0.001). NUP214-ABL1 was expressed in 16.6% of patients with TLX3-positive T-ALL (3 of 18); all of the patients with this association died before completion of the treatment. SILTAL expression did not significantly affect the prognosis of patients with T-cell acute lymphoblastic leukemia. Only three of 92 patients expressed the TLX1 gene and all three are alive. CONCLUSIONS: TLX3 gene expression is an independent risk factor predicting poor survival in childhood T-cell acute lymphoblastic leukemia. When co-expressed with TLX3, NUP214-ABL1 transcripts may increase the risk of poor survival.

Published
2008
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4. Analysis of the ethical issues raised by a ten-year epidemiology program in French Guiana: limitations of the current legal framework and solutions adopted

Author

Tortevoye, Patricia, Moutel, Grégoire, Tuppin, Philippe, Plancoulaine, Sabine, Joubert, Michel, Hervé, Christian, Gessain, Antoine, Epidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'éthique médicale et médecine légale (LEM), Université Paris Descartes - Paris 5 (UPD5)-Réseau Inserm de Recherche en éthique médicale, Institut de Veille Sanitaire (INVS), Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Coordination Centre de Santé, DASS, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'éthique médicale et médecine légale ( LEM ), Université Paris Descartes - Paris 5 ( UPD5 ) -Réseau Inserm de Recherche en éthique médicale, Institut de Veille Sanitaire ( INVS ), Génétique Humaine des Maladies Infectieuses ( Inserm U980 ), and Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 )

Subjects
MESH: Ethical Analysis, MESH: Poverty, Communication of the Results, MESH : Ethics, Research, Ethnicity, MESH: Informed Consent, Leukemia-Lymphoma, Adult T-Cell, MESH: Leukemia-Lymphoma, Adult T-Cell, MESH : HTLV-I Infections, Epidemiological studies, Informed Consent, MESH: Epidemiologic Studies, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, French Guiana, [ SDV.ETH ] Life Sciences [q-bio]/Ethics, Educational Status, MESH: Ethnic Groups, MESH : Poverty, France, MESH : Ethical Analysis, MESH : Ethnic Groups, MESH : French Guiana, Health Promotion, MESH : Epidemiologic Studies, Ethics, Research, MESH: HTLV-I Infections, MESH: French Guiana, Humans, Ethic, MESH : France, MESH: Ethics, Research, Poverty, Legal Limits, MESH: Humans, MESH : Consumer Participation, MESH : Humans, Community Participation, HTLV-I Infections, MESH : Leukemia-Lymphoma, Adult T-Cell, [SDV.ETH]Life Sciences [q-bio]/Ethics, MESH: France, Epidemiologic Studies, MESH: Consumer Participation, MESH : Informed Consent, HTLV-1, MESH : Health Promotion, MESH: Health Promotion, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Educational Status, Informatio, MESH : Educational Status, Ethical Analysis
Abstract

International audience; BACKGROUND: This paper discusses the ethical aspects of a large research program in virology, conducted since 1994 and which has evolved in parallel with the elaboration of bioethics laws in France. This research, which involved the collection of a considerable amount of epidemiological data in the field, focused on epidemiological determinants (mother to child transmission, genetic susceptibility/resistance) of the human oncogenic retrovirus human T cell lymphotropic virus type 1 (HTLV-1). Data were collected from a specific population (Noirs Marrons) living in remote areas in French Guiana (South America). This ethnic group of African descent is highly endemic for HTLV-1 and associated adult T cell leukemia/lymphoma. The population has lived for two centuries on either side of the Maroni river, which constitutes the frontier between French Guiana and Surinam. The low socioeconomic and education levels of a large part of this population are mainly explained by a recent housing/residence fixation on the French side of the Maroni river. It is also linked to significant immigration from Surinam due to the civil war, which lasted for five years in the late 1990s, in this country. Conducting epidemiological surveys in this peculiar context illustrates the limitations of the available current legal framework in France for such studies. Indeed, several important ethical issues arose concerning not only individual and population benefits, but also specificities of the given information and of the informed consent. Another question concerns individual information feed-back in such a context of persistent viral infection, with a very low disease incidence, in a population with a relatively low education level. The goal of this work was mainly to report several of the ethical issues encountered and to discuss possible ways of achieving better information deliver and consent procedures in such a context. Indeed, these procedures should include new ideas and regulations promoting a real partnership, in order to conduct long-term epidemiological studies in populations with a low education level.

Published
2007
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