Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice
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 ly...
| Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | article |
| Status: | Versión aceptada para publicación |
| Publication Date: | 2022 |
| Country: | España |
| Institution: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repository: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/278133 |
| Online Access: | http://hdl.handle.net/10261/278133 |
| Access Level: | Open access |
| Keyword: | Animals Carcinogenesis / genetics DNA Damage Gene Deletion Gene expression regulation Neoplastic Lymphoma B-Cell / genetics Mice Mice, Knockout Poly (ADP-Ribose) Polymerase-1 / genetics Poly(ADP-ribose) Polymerases / genetics Proto-Oncogene Proteins c-myc / genetics |
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Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice |
| title |
Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice |
| spellingShingle |
Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice Galindo-Campos, M. A. Animals Carcinogenesis / genetics DNA Damage Gene Deletion Gene expression regulation Neoplastic Lymphoma B-Cell / genetics Mice Mice, Knockout Poly (ADP-Ribose) Polymerase-1 / genetics Poly(ADP-ribose) Polymerases / genetics Proto-Oncogene Proteins c-myc / genetics |
| title_short |
Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice |
| title_full |
Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice |
| title_fullStr |
Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice |
| title_full_unstemmed |
Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice |
| title_sort |
Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice |
| dc.creator.none.fl_str_mv |
Galindo-Campos, M. A. Lutfi, Nuria Bonnin, S. Martínez, C. Velasco-Hernández, Talia García-Hernández, V. Martín Caballero, Juan Ampurdanés, Coral Gimeno, R. Colomo, L. Roué, Gaël Guilbaud, G. Dantzer, Françoise Navarro Medrano, Pilar Murga, Matilde Fernández-Capetillo, Óscar Bigas, A. Menéndez, Pablo Sale; J. E. |
| author |
Galindo-Campos, M. A. |
| author_facet |
Galindo-Campos, M. A. Lutfi, Nuria Bonnin, S. Martínez, C. Velasco-Hernández, Talia García-Hernández, V. Martín Caballero, Juan Ampurdanés, Coral Gimeno, R. Colomo, L. Roué, Gaël Guilbaud, G. Dantzer, Françoise Navarro Medrano, Pilar Murga, Matilde Fernández-Capetillo, Óscar Bigas, A. Menéndez, Pablo Sale; J. E. |
| author_role |
author |
| author2 |
Lutfi, Nuria Bonnin, S. Martínez, C. Velasco-Hernández, Talia García-Hernández, V. Martín Caballero, Juan Ampurdanés, Coral Gimeno, R. Colomo, L. Roué, Gaël Guilbaud, G. Dantzer, Françoise Navarro Medrano, Pilar Murga, Matilde Fernández-Capetillo, Óscar Bigas, A. Menéndez, Pablo Sale; J. E. |
| author2_role |
author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Ministerio de Industria y Competitividad (España) Ministerio de Ciencia e Innovación (España) Fundación Científica Asociación Española Contra el Cáncer Medical Research Council (UK) Laboratory of Excellence of Biology for Psychiatry (France) Université de Strasbourg Centre National de la Recherche Scientifique (France) Instituto de Salud Carlos III European Commission Generalitat de Catalunya Centres de Recerca de Catalunya Josep Carreras Leukemia Foundation Fundación Unoentrecienmil Marie Curie International Incoming Fellowship Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| dc.subject.none.fl_str_mv |
Animals Carcinogenesis / genetics DNA Damage Gene Deletion Gene expression regulation Neoplastic Lymphoma B-Cell / genetics Mice Mice, Knockout Poly (ADP-Ribose) Polymerase-1 / genetics Poly(ADP-ribose) Polymerases / genetics Proto-Oncogene Proteins c-myc / genetics |
| topic |
Animals Carcinogenesis / genetics DNA Damage Gene Deletion Gene expression regulation Neoplastic Lymphoma B-Cell / genetics Mice Mice, Knockout Poly (ADP-Ribose) Polymerase-1 / genetics Poly(ADP-ribose) Polymerases / genetics Proto-Oncogene Proteins c-myc / genetics |
| description |
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 E¿-Myc mouse model of aggressive B-cell lymphoma. Loss of PARP-2 aggravates replication stress in preleukemic E¿-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. |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022 2022 2022 2022 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Postprint info:eu-repo/semantics/acceptedVersion |
| format |
article |
| status_str |
acceptedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10261/278133 |
| url |
http://hdl.handle.net/10261/278133 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
#PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-83565-R info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-112526RB-I00 info:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (ISCIII)/PI17%2F00199 info:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI20%2F00625 info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-108160RB-I00 info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-102204-B-I00 info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104695RB-I00 Galindo-Campos, M. A.; Lutfi, Nuria; Bonnin, Sarah; Martínez, Carlos; Velasco-Hernández, Talia; García-Hernández, V.; Martín Caballero, Juan; Ampurdanés, Coral; Gimeno, Ramón; Colomo, Lluis; Roué, Gaël; Guilbaud, G.; Dantzer, Françoise; Navarro Medrano, Pilar; Murga, Matilde; Fernández-Capetillo, Óscar; Bigas, Anna; Menéndez, Pablo; Sale; J. E.; 2022; Supplementary Data Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice [Dataset]; American Society of Hematology; http://dx.doi.org/10.1182/blood.2021012805 http://dx.doi.org/10.1182/blood.2021012805 Sí |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
| dc.publisher.none.fl_str_mv |
American Society of Hematology |
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American Society of Hematology |
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reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC) |
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1869423211239702528 |
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Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in miceGalindo-Campos, M. A.Lutfi, NuriaBonnin, S.Martínez, C.Velasco-Hernández, TaliaGarcía-Hernández, V.Martín Caballero, JuanAmpurdanés, CoralGimeno, R.Colomo, L.Roué, GaëlGuilbaud, G.Dantzer, FrançoiseNavarro Medrano, PilarMurga, MatildeFernández-Capetillo, ÓscarBigas, A.Menéndez, PabloSale; J. E.AnimalsCarcinogenesis / geneticsDNA DamageGene DeletionGene expression regulationNeoplastic LymphomaB-Cell / geneticsMiceMice, KnockoutPoly (ADP-Ribose) Polymerase-1 / geneticsPoly(ADP-ribose) Polymerases / geneticsProto-Oncogene Proteins c-myc / geneticsDysregulation 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 E¿-Myc mouse model of aggressive B-cell lymphoma. Loss of PARP-2 aggravates replication stress in preleukemic E¿-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.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).Peer reviewedAmerican Society of HematologyMinisterio de Industria y Competitividad (España)Ministerio de Ciencia e Innovación (España)Fundación Científica Asociación Española Contra el CáncerMedical Research Council (UK)Laboratory of Excellence of Biology for Psychiatry (France)Université de StrasbourgCentre National de la Recherche Scientifique (France)Instituto de Salud Carlos IIIEuropean CommissionGeneralitat de CatalunyaCentres de Recerca de CatalunyaJosep Carreras Leukemia FoundationFundación UnoentrecienmilMarie Curie International Incoming FellowshipConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2022202220222022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttp://hdl.handle.net/10261/278133reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-83565-Rinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-112526RB-I00info:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (ISCIII)/PI17%2F00199info:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI20%2F00625info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-108160RB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-102204-B-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104695RB-I00Galindo-Campos, M. A.; Lutfi, Nuria; Bonnin, Sarah; Martínez, Carlos; Velasco-Hernández, Talia; García-Hernández, V.; Martín Caballero, Juan; Ampurdanés, Coral; Gimeno, Ramón; Colomo, Lluis; Roué, Gaël; Guilbaud, G.; Dantzer, Françoise; Navarro Medrano, Pilar; Murga, Matilde; Fernández-Capetillo, Óscar; Bigas, Anna; Menéndez, Pablo; Sale; J. E.; 2022; Supplementary Data Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice [Dataset]; American Society of Hematology; http://dx.doi.org/10.1182/blood.2021012805http://dx.doi.org/10.1182/blood.2021012805Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2781332026-05-22T06:33:51Z |
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