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| Pàgina inicial > Articles > Articles publicats > Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice |
(Institut Hospital del Mar d'Investigacions Mèdiques) (Centre de Regulació Genòmica) (Instituto Murciano de Investigación Biosanitaria) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Hospital del Mar d'Investigacions Mèdiques) (Laboratory of Immunology. Department of Pathology) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Division of Protein and Nucleic Acid Chemistry. Medical Research Council Laboratory of Molecular Biology) (Hospital del Mar Medical Research Institute. Unidad Asociada IIBB-CSIC) (Genomic Instability Group. Spanish National Cancer Research Centre) (Science for Life Laboratory. Department of Medical Biochemistry and Biophysics. Karolinska Institutet) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Laboratory of Immunology. Department of Pathology)
| Data: | 2022 |
| Resum: | Dysregulation of the c-Myc oncogene occurs in a wide variety of hematologic malignancies, and its overexpression has been linked with aggressive tumor progression. Here, we show that poly (ADP-ribose) polymerase 1 (PARP-1) and PARP-2 exert opposing influences on progression of c-Myc-driven B-cell lymphoma. PARP-1 and PARP-2 catalyze the synthesis and transfer of ADP-ribose units onto amino acid residues of acceptor proteins in response to DNA strand breaks, playing a central role in the response to DNA damage. Accordingly, PARP inhibitors have emerged as promising new cancer therapeutics. However, the inhibitors currently available for clinical use are not able to discriminate between individual PARP proteins. We found that genetic deletion of PARP-2 prevents c-Myc-driven B-cell lymphoma, whereas PARP-1 deficiency accelerates lymphomagenesis in the Eμ-Myc mouse model of aggressive B-cell lymphoma. Loss of PARP-2 aggravates replication stress in preleukemic Eμ-Myc B cells, resulting in accumulation of DNA damage and concomitant cell death that restricts the c-Myc-driven expansion of B cells, thereby providing protection against B-cell lymphoma. In contrast, PARP-1 deficiency induces a proinflammatory response and an increase in regulatory T cells, likely contributing to immune escape of B-cell lymphoma, resulting in an acceleration of lymphomagenesis. These findings pinpoint specific functions for PARP-1 and PARP-2 in c-Myc-driven lymphomagenesis with antagonistic consequences that may help inform the design of new PARP-centered therapeutic strategies, with selective PARP-2 inhibition potentially representing a new therapeutic approach for the treatment of c-Myc-driven tumors. |
| Ajuts: | Agencia Estatal de Investigación PID2020-112526RB-I00 Agencia Estatal de Investigación RTI2018-102204-B-I00 Agencia Estatal de Investigación SAF2017-83565-R Agencia Estatal de Investigación PID2019-104695RB-I00 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017-SGR-225 Instituto de Salud Carlos III PI17/00199 Instituto de Salud Carlos III PI20/00625 European Commission 617840 |
| Nota: | Fundació Carreras |
| Nota: | The J.Y. laboratory is funded by the Spanish Ministerio de Economía, Industria y Competitividad (grant SAF2017-83565-R), Spanish Ministerio de Ciencia e Innovación (grant PID2020-112526RB-I00), and Fundación Científica de la Asociación Española Contra el Cáncer (grant PROYEI6018YÉLA). Work in the J.E.S. laboratory is supported by a core grant to the Laboratory of Molecular Biology from the Medical Research Council (U105178808). The F.D. laboratory is supported by a Laboratory of Excellence grant (ANR-10-LABX-0034_Medalis) to Strasbourg University, Centre National de la Recherche Scientifique. The P.N. laboratory is supported by grants from the Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (FEDER; PI17/00199 and PI20/00625) and the Generalitat de Catalunya (2017-SGR-225). The P.M. laboratory acknowledges support from Centres de Recerca de Catalunya/Generalitat de Catalunya and Fundació Josep Carreras-Obra Social la Caixa for core support, the Spanish Ministry of Economy and Competitiveness (grant SAF-2019-108160-R), the Fundación Uno entre Cienmil, the Obra Social La Caixa (grant LCF/PR/HR19/52160011), and the German Josep Carreras Leukamie Stiftung. Work at the G.R. and P.M. laboratories are cofinanced by the European Regional Development Fund through the Interreg V-A Spain-France-Andorra Program (project PROTEOblood; grant EFA360/19). The O.F.-C. laboratory is funded by grants from the Spanish Ministry of Science, Innovation and Universities (RTI2018-102204-B-I00; cofinanced with European FEDER funds) and the European Research Council (ERC-617840). T.V.-H. was supported by a Marie Sklodowska Curie fellowship (GA792923). The A.B. laboratory is supported by the Spanish Ministry of Economy and Competitiveness (grant PID2019-104695RB-I00). |
| Nota: | The authors thank Raul Gomez-Riera for assistance with microscopic analysis, Mar?a Luisa Toribio for providing the HRSIN-ICN1 plasmid, Jessica Gonzalez for technical assistance, and the Flow Cytometry Unit and the Genomics Unit at the Centre for Genomic Regulation for assistance with Aseq at the Barcelona Biomedical Research Park. The J.Y. laboratory is funded by the Spanish Ministerio de Econom?a, Industria y Competitividad (grant SAF2017-83565-R), Spanish Ministerio de Ciencia e Innovaci?n (grant PID2020-112526RB-I00), and Fundaci?n Cient?fica de la Asociaci?n Espa?ola Contra el C?ncer (grant PROYEI6018Y?LA). Work in the J.E.S. laboratory is supported by a core grant to the Laboratory of Molecular Biology from the Medical Research Council (U105178808). The F.D. laboratory is supported by a Laboratory of Excellence grant (ANR-10-LABX-0034_Medalis) to Strasbourg University, Centre National de la Recherche Scientifique. The P.N. laboratory is supported by grants from the Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III?Fondo Europeo de Desarrollo Regional (FEDER; PI17/00199 and PI20/00625) and the Generalitat de Catalunya (2017-SGR-225). The P.M. laboratory acknowledges support from Centres de Recerca de Catalunya/Generalitat de Catalunya and Fundaci? Josep Carreras-Obra Social la Caixa for core support, the Spanish Ministry of Economy and Competitiveness (grant SAF-2019-108160-R), the Fundaci?n Uno entre Cienmil, the Obra Social La Caixa (grant LCF/PR/HR19/52160011), and the German Josep Carreras Leukamie Stiftung. Work at the G.R. and P.M. laboratories are cofinanced by the European Regional Development Fund through the Interreg V-A Spain-France-Andorra Program (project PROTEOblood; grant EFA360/19). The O.F.-C. laboratory is funded by grants from the Spanish Ministry of Science, Innovation and Universities (RTI2018-102204-B-I00; cofinanced with European FEDER funds) and the European Research Council (ERC-617840). T.V.-H. was supported by a Marie Sklodowska Curie fellowship (GA792923). The A.B. laboratory is supported by the Spanish Ministry of Economy and Competitiveness (grant PID2019-104695RB-I00). |
| Drets: | Tots els drets reservats.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Matèria: | Animals ; Carcinogenesis ; DNA Damage ; Gene Deletion ; Gene Expression Regulation, Neoplastic ; Lymphoma, B-Cell ; Mice ; Mice, Knockout ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases ; Proto-Oncogene Proteins c-myc |
| Publicat a: | Blood, Vol. 139 Núm. 2 (13 2022) , p. 228-239, ISSN 1528-0020 |
