Department of Medicine, Division of Hematology, Miller School of Medicine, University of Miami, 1600 NW 10th Avenue/1475 NW 12th Avenue (D8-4), Miami, FL 33136, USA.
Department of Medicine, Division of Hematology, Miller School of Medicine, University of Miami, 1600 NW 10th Avenue/1475 NW 12th Avenue (D8-4), Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
Cancer Cell. 2019 Sep 16;36(3):237-249.e6. doi: 10.1016/j.ccell.2019.07.007. Epub 2019 Aug 22.
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.
DNA 双链断裂 (DSB) 修复机制的缺陷已被广泛用于治疗多种恶性肿瘤，包括同源重组 (HR) 缺陷型乳腺癌和卵巢癌。在这里，我们证明表达 LMO2 蛋白的弥漫性大 B 细胞淋巴瘤 (DLBCL) 在 HR 介导的 DSB 修复中功能上存在缺陷。从机制上讲，LMO2 通过在修复过程中与 53BP1 相互作用来抑制 BRCA1 募集到 DSB。与 BRCA1 缺陷型细胞类似，LMO2 阳性的 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) 抑制剂具有高敏感性。此外，化疗和 PARP 抑制剂协同抑制 LMO2 阳性肿瘤的生长。总之，我们的研究结果表明，LMO2 的表达预测 HR 缺陷以及 PARP 抑制剂在 DLBCL 和 T-ALL 中的潜在治疗用途。
