Next-generation hypomethylating agent SGI-110 primes acute myeloid leukemia cells to IAP antagonist by activating extrinsic and intrinsic apoptosis pathways.,Cell Death and Differentiation

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Next-generation hypomethylating agent SGI-110 primes acute myeloid leukemia cells to IAP antagonist by activating extrinsic and intrinsic apoptosis pathways.
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2019-12-12 , DOI: 10.1038/s41418-019-0465-8
Jessica Dittmann ₁ , Tinka Haydn ₁ , Patrick Metzger _{2,

3,

4} , George A Ward ₅ , Melanie Boerries _{2,

3,

6,

7} , Meike Vogler ₁ , Simone Fulda _{1,

7,

8}

Affiliation

Therapeutic efficacy of first-generation hypomethylating agents (HMAs) is limited in elderly acute myeloid leukemia (AML) patients. Therefore, combination strategies with targeted therapies are urgently needed. Here, we discover that priming with SGI-110 (guadecitabine), a next-generation HMA, sensitizes AML cells to ASTX660, a novel antagonist of cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2) and X-linked IAP (XIAP). Importantly, SGI-110 and ASTX660 synergistically induced cell death in a panel of AML cell lines as well as in primary AML samples while largely sparing normal CD34+ human progenitor cells, underlining the translational relevance of this combination. Unbiased transcriptome analysis revealed that SGI-110 alone or in combination with ASTX660 upregulated the expression of key regulators of both extrinsic and intrinsic apoptosis signaling pathways such as TNFRSF10B (DR5), FAS, and BAX. Individual knockdown of the death receptors TNFR1, DR5, and FAS significantly reduced SGI-110/ASTX660-mediated cell death, whereas blocking antibodies for tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or FAS ligand (FASLG) failed to provide protection. Also, TNFα-blocking antibody Enbrel had little protective effect on SGI-110/ASTX660-induced cell death. Further, SGI-110 and ASTX660 acted in concert to promote cleavage of caspase-8 and BID, thereby providing a link between extrinsic and intrinsic apoptotic pathways. Consistently, sequential treatment with SGI-110 and ASTX660-triggered loss of mitochondrial membrane potential (MMP) and BAX activation which contributes to cell death, as BAX silencing significantly protected from SGI-110/ASTX660-mediated apoptosis. Together, these events culminated in the activation of caspases-3/-7, nuclear fragmentation, and cell death. In conclusion, SGI-110 and ASTX660 cooperatively induced apoptosis in AML cells by engaging extrinsic and intrinsic apoptosis pathways, highlighting the therapeutic potential of this combination for AML.

中文翻译：

新一代低甲基化剂 SGI-110 通过激活外在和内在凋亡途径，使急性髓系白血病细胞产生 IAP 拮抗剂。

第一代低甲基化药物（HMA）对老年急性髓系白血病（AML）患者的治疗效果有限。因此，迫切需要与靶向治疗相结合的策略。在这里，我们发现用新一代 HMA SGI-110（瓜地西他滨）启动可使 AML 细胞对 ASTX660 敏感，ASTX660 是凋亡蛋白 1 和 2 (cIAP1/2) 和 X 连锁 IAP (XIAP) 细胞抑制剂的新型拮抗剂）。重要的是，SGI-110 和 ASTX660 协同诱导一组 AML 细胞系以及原发性 AML 样本中的细胞死亡，同时很大程度上保留了正常 CD34+ 人类祖细胞，强调了这种组合的翻译相关性。无偏转录组分析显示，SGI-110单独或与ASTX660联合上调外在和内在细胞凋亡信号通路的关键调节因子的表达，例如TNFRSF10B (DR5)、FAS和BAX。单独敲低死亡受体 TNFR1、DR5 和 FAS 显着减少 SGI-110/ASTX660 介导的细胞死亡，而肿瘤坏死因子 (TNF) 相关凋亡诱导配体 (TRAIL) 或 FAS 配体 (FASLG) 的阻断抗体则失败提供保护。此外，TNFα 阻断抗体 Enbrel 对 SGI-110/ASTX660 诱导的细胞死亡几乎没有保护作用。此外，SGI-110 和 ASTX660 协同作用，促进 caspase-8 和 BID 的裂解，从而提供外在和内在凋亡途径之间的联系。一致地，SGI-110和ASTX660连续治疗会引发线粒体膜电位（MMP）损失和BAX激活，从而导致细胞死亡，因为BAX沉默可显着防止SGI-110/ASTX660介导的细胞凋亡。这些事件最终导致 caspase-3/-7 的激活、核碎裂和细胞死亡。总之，SGI-110 和 ASTX660 通过参与外在和内在凋亡途径协同诱导 AML 细胞凋亡，凸显了该组合对 AML 的治疗潜力。

更新日期：2019-12-13

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