期刊
BLOOD
卷 139, 期 2, 页码 228-239出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2021012805
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资金
- Spanish Ministerio de Econom?a, Industria y Competitividad [SAF2017-83565-R]
- Spanish Minis-terio de Ciencia e Innovaci?on [PID2020-112526RB-I00]
- Fundaci?on Cient?fica de la Asociaci?on Espan~ola Contra el Ca?ncer [PROYEI6018Y?ELA]
- Laboratory of Molecular Biology from the Med-ical Research Council [U105178808]
- Laboratory of Excellence grant [ANR-10-LABX-0034_Medalis]
- Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (FEDER) [PI17/00199, PI20/00625]
- Generalitat de Catalunya [2017-SGR-225]
- Centres de Recerca de Catalunya/Generalitat de Catalunya and Fundaci?o Josep Carreras-Obra Social la Caixa
- Spanish Ministry of Economy and Com-petitiveness [SAF-2019-108160-R]
- Fundaci?on Uno entre Cienmil, the Obra Social La Caixa [LCF/PR/HR19/52160011]
- German Josep Carreras Leukamie Stiftung
- European Regional Development Fund through the Interreg V-A Spain-France-Andorra Program [EFA360/19]
- Spanish Ministry of Science, Inno-vation and Universities [RTI2018-102204-B-I00]
- FEDER funds
- European Research Council [ERC-617840]
- Marie Sklodowska Curie fellow-ship [GA792923]
- Spanish Ministry of Economy and Competitiveness [PID2019-104695RB-I00]
Dysregulation of the c-Myc oncogene is linked to aggressive tumor progression, and PARP-1 and PARP-2 have opposing influence in c-Myc-driven B-cell lymphoma. PARP-1 deficiency accelerates lymphomagenesis, while genetic deletion of PARP-2 prevents B-cell lymphoma. These findings provide important insights for the design of new PARP-centered therapeutic strategies.
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 Em-Myc mouse model of aggressive B-cell lymphoma. Loss of PARP-2 aggravates replication stress in preleukemic Em-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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