Andrea Molina-Alvarez , Blanca Sanchez-Gonzalez , Luis Colomo , José Yélamos
{"title":"PARP-1和PARP-2在b细胞淋巴瘤中的致病作用和治疗意义","authors":"Andrea Molina-Alvarez , Blanca Sanchez-Gonzalez , Luis Colomo , José Yélamos","doi":"10.1016/j.ajpath.2025.07.004","DOIUrl":null,"url":null,"abstract":"<div><div>B-cell lymphomas represent a heterogeneous group of malignancies characterized by complex genetic, epigenetic, and microenvironmental alterations. Defects in the DNA damage response (DDR) are critical drivers of lymphomagenesis, generating therapeutic vulnerabilities that can be exploited by targeting key DDR regulators, such as poly (ADP-ribose) polymerase-1 (PARP-1) and PARP-2. Preclinical studies demonstrate that DDR-defective B-cell lymphomas are highly sensitive to PARP-1/PARP-2 inhibition, and early-phase clinical trials using nonselective PARP inhibitors, either as monotherapy or in combination with chemotherapy, immunotherapy, or epigenetic agents, have yielded encouraging results. However, emerging evidence reveals that PARP-1 and PARP-2 play distinct roles in B-cell lymphoma pathogenesis: loss of PARP-1 accelerates lymphomagenesis, whereas loss of PARP-2 delays tumor progression. These findings challenge the current paradigm of pan-PARP inhibition and highlight the need for isoform-selective strategies. Although PARP-1–selective inhibitors have entered clinical trials for homologous recombination–deficient tumors, the development of PARP-2–selective inhibitors remains at an early stage. Future research should prioritize the design of PARP-2–targeted therapies, coupled with biomarker-driven patient selection and rational combination strategies that enhance DNA damage and modulate the tumor immune microenvironment. Selectively targeting PARP-2 offers a promising approach to improving outcomes for patients with aggressive, refractory, or relapsed B-cell lymphomas and represents a critical step forward in advancing precision oncology within hematologic malignancies.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Pages 1776-1787"},"PeriodicalIF":3.6000,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Poly (ADP-Ribose) Polymerase 1 and 2 in B-Cell Lymphoma\",\"authors\":\"Andrea Molina-Alvarez , Blanca Sanchez-Gonzalez , Luis Colomo , José Yélamos\",\"doi\":\"10.1016/j.ajpath.2025.07.004\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>B-cell lymphomas represent a heterogeneous group of malignancies characterized by complex genetic, epigenetic, and microenvironmental alterations. Defects in the DNA damage response (DDR) are critical drivers of lymphomagenesis, generating therapeutic vulnerabilities that can be exploited by targeting key DDR regulators, such as poly (ADP-ribose) polymerase-1 (PARP-1) and PARP-2. Preclinical studies demonstrate that DDR-defective B-cell lymphomas are highly sensitive to PARP-1/PARP-2 inhibition, and early-phase clinical trials using nonselective PARP inhibitors, either as monotherapy or in combination with chemotherapy, immunotherapy, or epigenetic agents, have yielded encouraging results. However, emerging evidence reveals that PARP-1 and PARP-2 play distinct roles in B-cell lymphoma pathogenesis: loss of PARP-1 accelerates lymphomagenesis, whereas loss of PARP-2 delays tumor progression. These findings challenge the current paradigm of pan-PARP inhibition and highlight the need for isoform-selective strategies. Although PARP-1–selective inhibitors have entered clinical trials for homologous recombination–deficient tumors, the development of PARP-2–selective inhibitors remains at an early stage. Future research should prioritize the design of PARP-2–targeted therapies, coupled with biomarker-driven patient selection and rational combination strategies that enhance DNA damage and modulate the tumor immune microenvironment. Selectively targeting PARP-2 offers a promising approach to improving outcomes for patients with aggressive, refractory, or relapsed B-cell lymphomas and represents a critical step forward in advancing precision oncology within hematologic malignancies.</div></div>\",\"PeriodicalId\":7623,\"journal\":{\"name\":\"American Journal of Pathology\",\"volume\":\"195 10\",\"pages\":\"Pages 1776-1787\"},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2025-07-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American Journal of Pathology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0002944025002482\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PATHOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Pathology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0002944025002482","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PATHOLOGY","Score":null,"Total":0}
Poly (ADP-Ribose) Polymerase 1 and 2 in B-Cell Lymphoma
B-cell lymphomas represent a heterogeneous group of malignancies characterized by complex genetic, epigenetic, and microenvironmental alterations. Defects in the DNA damage response (DDR) are critical drivers of lymphomagenesis, generating therapeutic vulnerabilities that can be exploited by targeting key DDR regulators, such as poly (ADP-ribose) polymerase-1 (PARP-1) and PARP-2. Preclinical studies demonstrate that DDR-defective B-cell lymphomas are highly sensitive to PARP-1/PARP-2 inhibition, and early-phase clinical trials using nonselective PARP inhibitors, either as monotherapy or in combination with chemotherapy, immunotherapy, or epigenetic agents, have yielded encouraging results. However, emerging evidence reveals that PARP-1 and PARP-2 play distinct roles in B-cell lymphoma pathogenesis: loss of PARP-1 accelerates lymphomagenesis, whereas loss of PARP-2 delays tumor progression. These findings challenge the current paradigm of pan-PARP inhibition and highlight the need for isoform-selective strategies. Although PARP-1–selective inhibitors have entered clinical trials for homologous recombination–deficient tumors, the development of PARP-2–selective inhibitors remains at an early stage. Future research should prioritize the design of PARP-2–targeted therapies, coupled with biomarker-driven patient selection and rational combination strategies that enhance DNA damage and modulate the tumor immune microenvironment. Selectively targeting PARP-2 offers a promising approach to improving outcomes for patients with aggressive, refractory, or relapsed B-cell lymphomas and represents a critical step forward in advancing precision oncology within hematologic malignancies.
期刊介绍:
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.