坏死性凋亡在血液系统恶性疾病中的研究进展
Research Progress of Necroptosis in Hematological Malignant Diseases
DOI: 10.12677/ACM.2024.142401, PDF, HTML, XML, 下载: 134  浏览: 183 
作者: 王亚楠, 郝建萍*:新疆医科大学第一附属医院血液病中心,新疆 乌鲁木齐
关键词: 坏死性凋亡血液系统恶性疾病治疗Necroptosis Hematological Malignant Diseases Treatment
摘要: 坏死性凋亡是一种主要通过细胞内的信号传导途径调控的细胞死亡方式,在血液系统恶性疾病的发生和发展过程中发挥着重要作用。本文通过分析坏死性凋亡在血液系统恶性疾病中的潜在应用前景,探讨坏死性凋亡的调控机制和干预方法,有望为血液系统恶性疾病的治疗提供新的思路和策略。
Abstract: Necroptosis is a mode of cell death mainly regulated by intracellular signal transduction pathways, which plays an important role in the occurrence and development of hematological malignant dis-eases. By analyzing the potential application prospect of necroptosis in hematological malignant diseases, discussing the regulation mechanism and intervention methods of necroptosis, it is ex-pected to provide new ideas and strategies for the treatment of hematological malignant diseases.
文章引用:王亚楠, 郝建萍. 坏死性凋亡在血液系统恶性疾病中的研究进展[J]. 临床医学进展, 2024, 14(2): 2837-2842. https://doi.org/10.12677/ACM.2024.142401

1. 坏死性凋亡的发现

细胞死亡是调节细胞寿命和维持组织稳态的重要组成部分,细胞死亡主要分为2种类型,细胞坏死和细胞凋亡。传统观念认为坏死是被外界因素导致的偶然发生的细胞死亡形式,且不受机体调控,而细胞凋亡是可被机体管控的细胞死亡 [1] 。现有的研究发现,细胞凋亡不再是程序性细胞死亡的唯一方式。近年来深入研究的三种程序性细胞死亡途径是细胞凋亡 [2] 、焦亡 [3] 和坏死性凋亡 [4] 。

细胞焦亡在2001 [5] 年被发现。被称为半胱氨酸蛋白酶依赖性的细胞死亡,几种凋亡效应半胱氨酸蛋白酶(如Caspase-11、4/5和3)可引发细胞焦亡 [7] 。2005年,Degterev等 [6] 发现了一种可以被Necrostain-1 (NEC-1)所抑制的细胞死亡类型,发生在细胞凋亡受到抑制时 [8] [9] 表达坏死特征的程序性细胞死亡–坏死性凋亡(Necroptosis)。随着坏死性凋亡和细胞焦亡的发现,研究表明它们能够通过释放损伤相关分子模式(DAMP)和分泌白细胞介素(IL)-1β和IL-18等炎性细胞因子来触发炎症反应 [10] ,是程序性细胞死亡的炎症通路。

2. 坏死性凋亡的分子机制

在坏死性凋亡发生的过程中,坏死性凋亡可由多种刺激引起,包括死亡受体的配体、Toll样受体(TLR)、干扰素(IFN)受体和某些病原体。肿瘤坏死因子(TNF)被认为是坏死性凋亡的最重要诱因。TNF-α激活TNF受体1 (TNFR1)通过募集受体相互作用丝氨酸/苏氨酸蛋白激酶1 (RIPK1)、TNFR1相关死亡结构域蛋白(TRADD)、细胞凋亡抑制剂1/2 (cIAP1/2)和(TNFR相关因子2) TRAF2形成复合物I。在复合物I中,RIPK1被cIAP1/2泛素化,并最终激活核因子NF-κB信号通路。随后RIPK1与复合物I解离并被去泛素化酶(CYLD)去泛素化,然后Fas相关的死亡结构域蛋(FADD)和pro-caspase-8相互作用形成胞质蛋白复合物(复合物II)。该复合物激活Caspase-8,最终导致细胞凋亡。当Caspase-8活性受到抑制时,RIPK1-受体相互作用丝氨酸/苏氨酸蛋白激酶3 (RIPK3)-底物混合谱系激酶结构域样蛋白(MLKL)的典型死亡受体介导的坏死性凋亡途径在FADD的下游被激发。活化的RIPK1在包括FADD、Caspase-8和Caspase-10的寡聚复合物内募集,形成复合体II (Ripoptosome),然后磷酸化MLKL形成坏死小体(Necrosome)。MLKL寡聚体移位至质膜中富含磷酸化的磷脂酰肌醇磷酸(PIP)结合的位点与细胞质膜结合,并形成大孔,通过允许离子流入、细胞肿胀和膜溶解导致坏死性细胞死亡,随后细胞内的细胞质中的损伤相关分子模式(DAMPs)被释放,导致组织炎症和器官损伤 [11] 。目前研究表明坏死性凋亡信号通路在肿瘤发展、肿瘤坏死、肿瘤转移和肿瘤免疫应答中发挥作用 [12] 。因此我们在这里讨论在恶性血液系统疾病中坏死性凋亡是如何调节疾病的发生与发展。

3. 坏死性凋亡与血液系统恶性疾病

急性髓系白血病(AML)是一种造血祖细胞的异质性克隆性疾病,其自然病程仅有数月,发病率为3.7/100,000人,且高危患者5年内生存率不到15% [13] [14] 。由于凋亡相关蛋白表达失调,AML细胞可以逃逸细胞凋亡 [15] 。Nugues [16] 等人发现在AML患者中,RIPK3的表达显著降低。在小鼠AML细胞系中RIPK3在半胱天冬酶抑制剂作用下诱导细胞凋亡和坏死性凋亡。在WEHI-3bAML细胞系或小鼠胚胎成纤维细胞中转染RIPK3也会导致细胞死亡增加。具有无活性激酶结构域(RIPK3-kinase dead, RIPK3-KD)的RIPK3突变体的再表达诱导的细胞凋亡明显增加。说明RIPK3激酶结构域是AML细胞凋亡的重要调节因子。RIP3-KD的表达诱导了p65/RelA核因子-κB (NF-κB)亚基半胱天冬酶依赖性切割。AML细胞中的RIPK3沉默导致抑制坏死性凋亡和NF-κB活性的复合调节。Lui [17] 等人发现当zVAD-fmk抑制半胱天冬酶活性时,依托泊苷可以触发AML细胞中的cIAP 1/2和XIAP耗竭、促进(高迁移率族蛋白1) HMGB1的释放,激活NF-κB通路并促进细胞活力,还通过NF-κB通路负调控AML细胞坏死性凋亡 [18] 。Safferthal等 [19] 发现,拮抗IAP蛋白的Smac模拟物(例如BV6)通过以TNFα依赖性方式诱导坏死性凋亡来规避AML细胞凋亡耐药性的。Li [20] 等发现RIPK1抑制剂22b可显著增强低剂量西达本胺对细胞系和原代细胞的抗白血病作用,在皮下异种移植AML模型中,22b和西达本胺的组合表现出明显升高的抗肿瘤活性。22b和西达本胺的联合治疗可能是FLT3-ITD阳性AML患者的新治疗途径。Dan [21] 等发现Skp2和RIPK1在AML中呈高表达,Skp2通过减少K63连接的泛素与RIPK1的相互作用来调节RIPK1的功能,敲低Skp2可以抑制RIPK1转录调控,且在AML细胞中Skp2的缺失抑制PIPK1的表达。RIPK1表达降低后负性激活Akt/GSK3β。RIPK1也通过与RARα相互作用,增加RA信号传导靶基因C/EBPα和C/EBPβ来调节白血病细胞分化,Skp2-Akt/GSK3β-RIPK1通路有望成为AML的治疗方向。以上研究表明坏死性凋亡在急性髓系白血病的发生发展中起到了重要作用,为其治疗提供了潜在靶点。

在急性淋巴细胞白血病(ALL)中,对于一线化疗药物包括糖皮质激素耐药是导致ALL预后差的重要因素。McComb [22] 等使用小分子SMAC模拟物birinapant激活坏死性凋亡消除了来自高抗性ALL患者的样品中的难治性白血病细胞。Bonapace [23] 等发现泛BCL2抑制剂obatoclax通过触发了自噬依赖性坏死性凋亡,从而恢复了类固醇抗性ALL中对糖皮质激素地塞米松的应答。以上研究表明,在急性淋巴细胞白血病中可以通过激活坏死性凋亡恢复对一线治疗的耐药性。慢性淋巴细胞白血病(CLL)特征在于B淋巴细胞的单克隆CD5阳性亚群的进行性积累。高水平的淋巴结增强子结合因子1 (LEF1)是Wnt/3-catenin (连环蛋白)信传导的下游因子,也是CYLD的转录抑制因子,提示了CLL患者的不良预后。Xu [24] 等通过敲低CLL细胞中CXCL-1基因使LEF-1的转录和翻译表达均下调,而亚硒酸钠可抑制CXCL-1的表达,并与TNF-α、z-VAD联合作用,帮助CLL细胞恢复坏死性凋亡。为治疗慢性淋巴细胞白血病的提供了潜在药物。

非霍奇金淋巴瘤(NHL)是最常见的血液系统肿瘤,在初治缓解率高但易复发。Cerhan等 [25] 发现在NHL患者RIPK3、TNF-α及TLR的表达增加。CD30是肿瘤坏死因子受体的成员,在间变性大细胞淋巴瘤(ALCL)的肿瘤细胞中表达。Hirsc [26] 等发现在典型的NF-κB抑制或蛋白酶体抑制的情况下,CD30刺激诱导ALCL细胞的半胱天冬酶依赖性细胞死亡。然而,CD30是一种缺乏死亡结构域的TNF受体,无法募集死亡诱导复合物。在阻断RIPK1或使用NEC-1抑制RIPK1可以阻止CD30诱导的细胞死亡。RIPK1确定为CD30诱导的细胞死亡的关键介质,同时具有细胞凋亡和坏死性凋亡的特征。ALCL肿瘤细胞中RIPK1的表达可能符合CD30抗体与NF-κB/蛋白酶体抑制剂联合使用的治疗应用条件,为ALCL的针对性治疗提供了新的方向。伯基特淋巴瘤(BL)是一种高度侵袭性的B细胞非霍奇金淋巴瘤,预后差。Koch [27] 等发现当Z-VAD-fmk抑制半胱天冬酶活性时,Smac模拟物BV 6和TRAIL的组合治疗触发BL中的坏死性凋亡(TBZ治疗)。BL细胞对TBZ的敏感性与MLKL表达相关。MLKL启动子的甲基化状态分析揭示了甲基化与MLKL表达之间的相关性。提示了MLKL在BL中受到表观遗传学调控,可能作为基于坏死性凋亡的治疗成功的预后标志物。这些发现对BL新治疗方案的开发具有重要意义。

多发性骨髓瘤(MM)是一种以骨髓中浆细胞异常克隆为特征的血液系统恶性疾病,临床上目前暂无根治方法 [28] 。Chen [29] 等发现omega3多不饱和脂肪酸DHA/EPA和蛋白酶体抑制剂硼替佐米以独立RIPK3的方式诱导人MM细胞坏死。MLKL的磷酸化似乎不是MM细胞坏死诱导的必要条件。用细胞毒性化合物处理MM细胞可诱导MLKL裂解,活化的caspase-3/8/10同样可触发MLKL的蛋白裂解,而MLKL中Asp140Ala的突变阻断了这种裂解。泛caspase抑制剂ZVAD-FMK可有效防止DHA/EPA和硼替佐米诱导的细胞死亡。Xu等 [30] 发现KIAA1191 (一种依赖于NAPDH的氧化还原酶,在参与氧化 [31] 时可产生ROS)高表达可以抑制MM细胞的增殖和迁移,上调RIPK1、RIPK和CYL的表达,恢复TNF-α/z-VAD诱导的坏死性凋亡。且KIAA1191高表达与硼替佐米对MM细胞的增殖能力具有协同作用。这些发现为MM的药物治疗提出了新的方向。

骨髓增生异常综合征(MDS)是一组起源于造血干细胞的异质性髓系克隆性疾病,其特征是骨髓的无效造血,伴有不同程度的异型增生、血细胞减少和发展为急性髓系白血病的风险 [32] 。Wagner [33] 等发现小鼠造血细胞中坏死性凋亡的失调会诱发全身炎症并耗尽小鼠造血干细胞和祖细胞,导致骨髓衰竭,使小鼠骨髓出现MDS样改变。在这些小鼠模型中抑制坏死性凋亡或炎症信号可恢复造血并显著延缓骨髓衰竭。Zou [34] 等在MDS患者发现RIPK1和pMLKL的表达显著增加,而caspase-3的表达没有显著增加,且上述现象在早期/低级别MDS中最为明显。Montalban-Bravo [35] 等同样发现MDS患者MLKL表达水平显著升高,而RIPK1和RIPK3则没有显著上调。且MLKL表达水平较高与诊断时血红蛋白水平较低相关。去甲基化(HMA)治疗后观察到MLKL水平显著降低。而较高的RIPK1表达与较短的生存期相关。进一步支持了坏死性凋亡在MDS中的作用,以及HMAs和预后的潜在反应。表明坏死性凋亡是MDS潜在的治疗靶点,并可能用于可能导致MDS的其他遗传性疾病,为MDS患者提供临床益处。

4. 总结

综上所述,坏死性凋亡在血液系统恶性疾病的发生发展过程中起到了重要的作用,通过激活坏死性凋亡可以增加逃逸凋亡的肿瘤细胞的死亡及对化疗药物的敏感性,提高治疗效果,改善疾病预后,为寻找血液系统恶性疾病的治疗方案提供了新思路。

NOTES

*通讯作者。

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