Bortezomib-induced "BRCAness" sensitizes multiple myeloma cells to PARP inhibitors
Bortezomib-induced "BRCAness" sensitizes multiple myeloma cells to PARP inhibitors
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DOI：
10.1182/blood-2011-06-363911
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发表时间：
2011-12-08
期刊：
影响因子：
20.3
通讯作者：
Bahlis, Nizar J.
中科院分区：
文献类型：
--
作者：
Neri, Paola;Ren, Li;Bahlis, Nizar J.
染色体不稳定是克隆性骨髓瘤浆细胞的一个显著特征，它会导致基因组异常的永久积累。除了在蛋白质动态平衡中的作用外，泛素-蛋白酶体系统也参与了DNA损伤修复蛋白的调节。在本研究中，我们发现蛋白酶体抑制诱导骨髓瘤细胞(MM)处于“BRCAness”状态，其核内泛素库的耗尽和H_2AX多泛素化的取消是BRCA1和RAD51重新聚集到DNA双链断裂(DSB)和启动同源重组(HR)介导的DNA修复的关键步骤。用ABT-888抑制多聚腺苷二磷酸核糖聚合酶1和2(PARP1/2)可引起瞬时DNA双链断裂，这些双链断裂可迅速分解，因此对MM细胞的存活率没有影响。与之相反，与Bortezomib和ABT-888共同处理MM细胞株和原代CD138(+)细胞后，未修复的DNADSB持续积聚，并持续存在非泛素化的γ-H AX焦点，BRCA1和RAD51缺乏募集，从而导致MM细胞死亡。在SCID小鼠的多发性骨髓瘤移植瘤中，ABT-888与Bortezomib联合应用的细胞毒性也比单独使用任何一种药物都要高。我们的研究表明，Bortezomib损害MM的HR，并在与PARP抑制剂联合使用时导致上下文合成死亡。(血。2011；118(24)：6368-6379)
Chromosomal instability is a defining feature of clonal myeloma plasma cells that results in the perpetual accumulation of genomic aberrations. In addition to its role in protein homeostasis, the ubiquitin-proteasome system is also involved in the regulation of DNA damage-repair proteins. In the present study, we show that proteasome inhibition induces a "BRCAness" state in myeloma cells (MM), with depletion of their nuclear pool of ubiquitin and abrogation of H2AX polyubiquitylation, an essential step for the recruitment of BRCA1 and RAD51 to the sites of DNA double-stranded breaks (DSBs) and the initiation of homologous recombination (HR)-mediated DNA repair. Inhibition of poly-ADP-ribose-polymerase 1 and 2 (PARP1/2) with ABT-888 induced transient DNA DSBs that were rapidly resolved and thus had no effect on viability of the MM cells. In contrast, cotreatment of MM cell lines and primary CD138(+) cells with bortezomib and ABT-888 resulted in the sustained accumulation of unrepaired DNADSBs with persistence of unubiquitylated gamma H2AX foci, lack of recruitment of BRCA1 and RAD51, and ensuing MM-cell death. The heightened cytotoxicity of ABT-888 in combination with bortezomib compared with either drug alone was also confirmed in MM xenografts in SCID mice. Our studies indicate that bortezomib impairs HR in MM and results in a contextual synthetic lethality when combined with PARP inhibitors. (Blood. 2011;118(24):6368-6379)