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...

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Detalles Bibliográficos
Autores: Galindo Campos, Miguel A.|||0000-0002-0650-8660, Lutfi, Nura, Bonnin, Sarah|||0000-0001-5159-2518, Martínez Cáceres, Carlos|||0000-0003-3307-1326, Velasco-Hernández, Talia|||0000-0003-2183-7443, García-Hernández, Violeta|||0000-0003-2328-4360, Martín Caballero, Juan, Ampurdanés, Coral, Gimeno, Ramón|||0000-0002-8758-121X, Colomo, Luis|||0000-0001-5236-5085, Roué, Gaël|||0000-0003-0245-2257, Guilbaud, Guillaume|||0000-0002-4345-6855, Dantzer, Françoise, Navarro, Pilar|||0000-0003-4314-4584, Murga, Matilde|||0000-0002-9766-4481, Fernández Capetillo, Oscar|||0000-0002-2690-6885, Bigas Salvans, Anna|||0000-0003-4801-6899, Menéndez Bujan, Pablo|||0000-0001-9372-1007, Sale, Julian E., Yélamos, José|||0000-0003-1195-1496
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:289215
Acceso en línea:https://ddd.uab.cat/record/289215
https://dx.doi.org/urn:doi:10.1182/blood.2021012805
Access Level:acceso abierto
Palabra clave: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
Descripción
Sumario: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.

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