LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL
LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL
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DOI：
10.1016/j.ccell.2019.07.007
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发表时间：
2019-09-16
期刊：
影响因子：
50.3
通讯作者：
Lossos, Izidore S.
中科院分区：
文献类型：
--
作者：
Parvin, Salma;Ramirez-Labrada, Ariel;Lossos, Izidore S.
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。在这里，我们证明，弥漫性大B细胞淋巴瘤（DLBCL）表达LMO 2蛋白在HR介导的DSB修复功能缺陷。在机制上，LMO 2通过在修复过程中与53 BP 1相互作用来抑制BRCA 1向DSB的募集。与BRCA 1缺陷细胞类似，LMO 2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LMO 2阳性肿瘤的生长。总之，我们的研究结果表明，LMO 2表达预测HR缺陷和PARP抑制剂在DLBCL和T-ALL中的潜在治疗用途。
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.