The TP53 Apoptotic Network Is a Primary Mediator of Resistance to BCL2 Inhibition in AML Cells
The TP53 Apoptotic Network Is a Primary Mediator of Resistance to BCL2 Inhibition in AML Cells
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DOI：
10.1158/2159-8290.cd-19-0125
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发表时间：
2019-07-01
期刊：
影响因子：
28.2
通讯作者：
Tyner, Jeffrey W.
中科院分区：
文献类型：
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作者：
Nechiporuk, Tamilla;Kurtz, Stephen E.;Tyner, Jeffrey W.
为了研究急性髓系白血病 (AML) 对 BCL2 抑制剂 Venetoclax 耐药的潜在机制，我们使用全基因组 CRISPR/Cas9 筛选来识别导致耐药性的基因敲除。我们验证了 TP53、BAX 和 PMAIP1 基因的失活会导致 AML 细胞系中的维奈托克耐药。对 Venetoclax 的耐药性是由于 BAX 缺失、BCL2 表达减少和/或对替代 BCL2 家族成员（如 BCL2L1）的依赖导致无法执行细胞凋亡。这种抵抗伴随着线粒体稳态和细胞代谢的变化。对 TP53 敲除细胞对一组小分子抑制剂敏感性的评估显示，对 TRK 抑制剂的敏感性有所增加。我们将这些观察结果与 Beat AML 数据集中的患者药物反应和基因表达联系起来。我们的结果表明 TP53、细胞凋亡网络和线粒体功能是 AML 中维奈托克反应的驱动因素，并提出了克服耐药性的策略。 意义：由于其异质性，AML 的治疗具有挑战性，单药治疗普遍失败，因此需要创新的药物组合。我们使用遗传方法来识别失活导致耐药性的基因，以此作为形成首选药物组合以改善 AML 治疗的一种手段。
To study mechanisms underlying resistance to the BCL2 inhibitor venetoclax in acute myeloid leukemia (AML), we used a genome-wide CRISPR/Cas9 screen to identify gene knockouts resulting in drug resistance. We validated TP53, BAX, and PMAIP1 as genes whose inactivation results in venetoclax resistance in AML cell lines. Resistance to venetoclax resulted from an inability to execute apoptosis driven by BAX loss, decreased expression of BCL2, and/or reliance on alternative BCL2 family members such as BCL2L1. The resistance was accompanied by changes in mitochondrial homeostasis and cellular metabolism. Evaluation of TP53 knockout cells for sensitivities to a panel of small-molecule inhibitors revealed a gain of sensitivity to TRK inhibitors. We relate these observations to patient drug responses and gene expression in the Beat AML dataset. Our results implicate TP53, the apoptotic network, and mitochondrial functionality as drivers of venetoclax response in AML and suggest strategies to overcome resistance.SIGNIFICANCE: AML is challenging to treat due to its heterogeneity, and single-agent therapies have universally failed, prompting a need for innovative drug combinations. We used a genetic approach to identify genes whose inactivation contributes to drug resistance as a means of forming preferred drug combinations to improve AML treatment.