美国迈阿密大学的Izidore S. Lossos和Ramiro E. Verdun研究团队合作发现，LMO2对DLBCL中PARP的抑制作用具有合成致死率。2019年8月22日，国际知名学术期刊《癌细胞》在线发表了这一成果。

研究人员发现，表达LMO2蛋白的弥漫性大B细胞淋巴瘤（DLBCL）在HR介导的DSB修复中功能缺陷。在机制上，在修复期间LMO2通过与53BP1相互作用来抑制BRCA1向DSB的招募。与BRCA1缺陷细胞类似，LMO2阳性DLBCL和T细胞急性淋巴细胞白血病（T-ALL）细胞对聚（ADP-核糖）聚合酶（PARP）抑制剂表现出高度敏感性。此外，化疗和PARP抑制剂协同抑制LMO2阳性肿瘤的生长。总之，这些结果揭示了LMO2的表达能够预测HR缺乏以及PARP抑制剂在DLBCL和T-ALL中的潜在治疗用途。

研究人员表示，DNA双链断裂（DSB）修复机制的缺陷已被广泛用于治疗不同的恶性肿瘤，包括同源重组（HR）缺陷的乳腺癌和卵巢癌。

附：英文原文

Title: LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL

Author: Salma Parvin,Ariel Ramirez-Labrada,Shlomzion Aumann,XiaoQing Lu,Natalia Weich,Gabriel Santiago,Elena M. Cortizas,Eden Sharabi,Yu Zhang,Isidro Sanchez-Garcia,Andrew J. Gentles,Evan Roberts,Daniel Bilbao-Cortes,Francisco Vega,Jennifer R. Chapman,Ramiro E. Verdun,Izidore S. Lossos

Issue&Volume: 22 August 2019

Abstract: Deficiency in DNA double-strand break (DSB) repair mechanisms has been widely exploited for the treatment of different malignances, including homologous recombination (HR)-deficient breast and ovarian cancers. Here we demonstrate that diffuse large B cell lymphomas (DLBCLs) expressing LMO2 protein are functionally deficient in HR-mediated DSB repair. Mechanistically, LMO2 inhibits BRCA1 recruitment to DSBs by interacting with 53BP1 during repair. Similar to BRCA1-deficient cells, LMO2-positive DLBCLs and T cell acute lymphoblastic leukemia (T-ALL) cells exhibit a high sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Furthermore, chemotherapy and PARP inhibitors synergize to inhibit the growth of LMO2-positive tumors. Together, our results reveal that LMO2 expression predicts HR deficiency and the potential therapeutic use of PARP inhibitors in DLBCL and T-ALL.

DOI: https://doi.org/10.1016/j.ccell.2019.07.007

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30334-4#