ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies.
ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies.
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DOI：
10.1126/scisignal.aac4380
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发表时间：
2016-02-16
影响因子：
7.3
通讯作者：
Andreeff M
中科院分区：
文献类型：
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作者：
Ishizawa J;Kojima K;Chachad D;Ruvolo P;Ruvolo V;Jacamo RO;Borthakur G;Mu H;Zeng Z;Tabe Y;Allen JE;Wang Z;Ma W;Lee HC;Orlowski R;Sarbassov dos D;Lorenzi PL;Huang X;Neelapu SS;McDonnell T;Miranda RN;Wang M;Kantarjian H;Konopleva M;Davis RE;Andreeff M
血液恶性肿瘤中 p53 异常带来的临床挑战需要标准基因毒性化疗以外的治疗策略。 ONC201是一种一流的小分子，可激活不依赖于p53的细胞凋亡，具有良好的安全性，目前正处于早期临床试验阶段。我们发现 ONC201 在细胞系以及套细胞淋巴瘤 (MCL) 和急性髓系白血病 (AML) 患者样本中引起 p53 独立的细胞凋亡和细胞周期停滞；其中包括来自与不良预后相关的遗传异常患者的样本，或来自对非基因毒性药物依鲁替尼和硼替佐米产生耐药性的细胞的样本。此外，ONC201 引起干细胞和祖细胞 AML 细胞凋亡，并消除小鼠体内白血病干细胞的植入，同时不影响正常骨髓细胞。 ONC201引起的基因表达变化类似于未折叠蛋白反应（UPR）和整合应激反应（ISR）引起的变化，通过增加翻译起始因子eIF2α的磷酸化来增加转录因子ATF4的翻译。然而，与 UPR 和 ISR 不同，ONC201 处理的造血细胞中 ATF4 丰度的增加促进了细胞凋亡，并且不依赖于 eIF2α 磷酸化的增加。 ONC201 还抑制哺乳动物雷帕霉素靶复合物 1 (mTORC1) 信号传导，可能是通过 ATF4 介导的 mTORC1 抑制剂 DDIT4 的诱导。 BCL-2 的过表达可防止 ONC201 诱导的细胞凋亡，而 ONC201 和 BCL-2 拮抗剂 ABT-199 的组合可协同增加细胞凋亡。因此，我们的结果表明，通过诱导非典型 ISR 和 p53 独立的细胞凋亡，ONC201 在血液恶性肿瘤中具有临床潜力。
The clinical challenge posed by p53 abnormalities in hematological malignancies requires therapeutic strategies other than standard genotoxic chemotherapies. ONC201 is a first-in-class small molecule that activates p53-independent apoptosis, has a benign safety profile, and is in early clinical trials. We found that ONC201 caused p53-independent apoptosis and cell cycle arrest in cell lines and in mantle cell lymphoma (MCL) and acute myeloid leukemia (AML) samples from patients; these included samples from patients with genetic abnormalities associated with poor prognosis or cells that had developed resistance to the nongenotoxic agents ibrutinib and bortezomib. Moreover, ONC201 caused apoptosis in stem and progenitor AML cells and abrogated the engraftment of leukemic stem cells in mice while sparing normal bone marrow cells. ONC201 caused changes in gene expression similar to those caused by the unfolded protein response (UPR) and integrated stress responses (ISRs), which increase the translation of the transcription factor ATF4 through an increase in the phosphorylation of the translation initiation factor eIF2α. However, unlike the UPR and ISR, the increase in ATF4 abundance in ONC201-treated hematopoietic cells promoted apoptosis and did not depend on increased phosphorylation of eIF2α. ONC201 also inhibited mammalian target of rapamycin complex 1 (mTORC1) signaling, likely through ATF4-mediated induction of the mTORC1 inhibitor DDIT4. Overexpression of BCL-2 protected against ONC201-induced apoptosis, and the combination of ONC201 and the BCL-2 antagonist ABT-199 synergistically increased apoptosis. Thus, our results suggest that by inducing an atypical ISR and p53-independent apoptosis, ONC201 has clinical potential in hematological malignancies.