Acquired resistance to venetoclax (ABT-199) in t(14;18) positive lymphoma cells.
Acquired resistance to venetoclax (ABT-199) in t(14;18) positive lymphoma cells.
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DOI：
10.18632/oncotarget.12132
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发表时间：
2016-10-25
期刊：
影响因子：
--
通讯作者：
Hsi ED
中科院分区：
文献类型：
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作者：
Bodo J;Zhao X;Durkin L;Souers AJ;Phillips DC;Smith MR;Hsi ED
滤泡性淋巴瘤（FL）中的染色体易位t（14;18）是导致BCL-2过度表达的主要致癌事件。本研究探讨了BH 3模拟维奈托克（ABT-199），其目标BCL-2的活性，以及FL中获得性耐药的机制。FL细胞对维奈托克治疗的敏感性与BCL-2/BIM比值相关。抗凋亡蛋白表达相似但BIM水平较高的细胞对治疗更敏感。维奈托克诱导BCL-2/BIM复合物的解离和线粒体电位的降低。有趣的是，维奈托克处理后存活的细胞群显示p-ERK 1/2和p-BIM（S69）增加，以及总BIM水平降低。维奈托克耐药细胞最初显示p-AKT和p-Foxo 1/3a水平升高，BIM/BCL-2/BECLIN 1复合物解离，SQSTM 1/p62水平降低（表明自噬增加），BIM表达轻微下降。建立稳定的耐药细胞系后，观察到BCL-2水平显著降低，几乎完全不存在BIM。这些耐药表型的获得可以通过选择性ERK/AKT抑制或抗CD 20抗体治疗来预防，从而突出了FL患者可能的联合治疗。
The chromosomal translocation t(14;18) in follicular lymphoma (FL) is a primary oncogenic event resulting in BCL-2 over-expression. This study investigates activity of the BH3 mimetic venetoclax (ABT-199), which targets BCL-2, and mechanisms of acquired resistance in FL. The sensitivity of FL cells to venetoclax treatment correlated with BCL-2/BIM ratio. Cells with similar expression of anti-apoptotic proteins, but with higher levels of BIM were more sensitive to the treatment. Venetoclax induced dissociation of BCL-2/BIM complex and a decrease in mitochondrial potential. Interestingly the population of cells that survived venetoclax treatment showed increased p-ERK1/2 and p-BIM (S69), as well as a decrease in total BIM levels. Venetoclax resistant cells initially showed elevated levels of p-AKT and p-Foxo1/3a, a dissociation of BIM/BCL-2/BECLIN1 complex, and a decrease in SQSTM1/p62 level (indicating increased autophagy) together with a slight decline in BIM expression. After stable resistant cell lines were established, a significant reduction of BCL-2 levels and almost total absence of BIM was observed. The acquisition of these resistance phenotypes could be prevented via selective ERK/AKT inhibition or anti-CD20 antibody treatment, thus highlighting possible combination therapies for FL patients.