急性淋巴细胞白血病(acute lymphoblastic leukemia, ALL)是儿童时期最常见的恶性肿瘤,目前其治疗仍以联合化疗为主[1-3]。儿童ALL的治疗效果明显优于成人,近年来欧美发达国家报道儿童ALL的5年生存率已达90%[3-4]。虽然随着化疗方案的不断完善儿童ALL的无病生存率明显增加,但部分对常规化疗不敏感的患儿仍需引起我们关注。针对这部分患者往往需要增加药物剂量、种类以及延长化疗时间,然而化疗方案增强又增加药物副作用,降低生活质量。所以,对于耐药ALL的治疗仍是白血病治疗中的一个棘手问题。近年来相关研究证实BIM基因是一种能够介导淋巴细胞凋亡的促凋亡基因,该基因及其表达产物与ALL对糖皮质激素(glucocorticoid, GC)耐药有关[5-7]。
1 GC在儿童白血病治疗过程中的应用GC在儿童ALL的化疗中广泛应用,是目前化疗方案中的关键药物之一。据报道,GC应用于儿童ALL的治疗已经有超过50年的历史[8],且在激素诱导阶段结束后通过外周血及骨髓的原始细胞计数可判断ALL的预后[3, 8-11]。然而关于儿童ALL对GC耐药的报道并不少见,针对这类患儿通过有效措施恢复其对GC的敏感性能明显改善预后[7, 12]。说明GC在儿童ALL的治疗过程中发挥重要作用且与ALL的预后相关,采取有效的干预措施增加GC耐药ALL患儿对激素的敏感性可能是改善其预后的方法之一。
2 BIM基因简介近10余年来,BIM(Bcl-2 interacting mediator of cell death)作为Bcl-2(B cell leukemia/lymphoma-2 genes)家族的促凋亡基因被广泛深入研究。Bcl-2家族分为抗凋亡和促凋亡成员两部分,其中抗凋亡成员包括Bcl-2、Bcl-XL、Bcl-W、Mcl-1等,促凋亡成员主要包括BIM、PUMA、BAD、BID、BIK、NOXA等,抗凋亡及促凋亡成员通过相互作用发挥调节细胞凋亡的作用[13-14]。其中,促凋亡基因BIM通过表达仅含BH3结构域的蛋白质发挥重要的促凋亡功能,该基因也是目前被证实能在淋巴细胞中被GC诱导表达上调的Bcl-2家族成员[5-8, 14]。
3 BIM基因在细胞凋亡过程中的作用BIM基因的表达直接或者间接在细胞内源性凋亡的过程中发挥重要作用[14]。目前已经证实大量的刺激因素通过BIM介导的内源性凋亡途径引起细胞凋亡,这些刺激包括:细胞因子[15]或生长因子[16]突然撤退、缺乏葡萄糖的供应[17-19]、使用酪氨酸激酶抑制剂[20]、GC[21-23]、热休克蛋白[13, 24]等。Ploner等[25]通过体外实验证实,GC诱导的CCRF-CEM细胞凋亡与BIM基因敲除有关,相关研究也证实BIM基因在GC介导的白血病细胞凋亡过程中发挥关键作用[26-28]。从而说明GC介导的BIM基因表达与正常及恶变的淋巴细胞凋亡有关。
4 BIM基因及其表达产物在GC治疗儿童ALL中的作用 4.1 BIM基因在GC治疗ALL过程中的作用在研究ALL对GC耐药机制的过程中,Bcl-2家族成员因在GC介导的淋巴细胞凋亡过程中发挥关键的促凋亡功能而被广泛研究[10, 29-31]。Kfir-Erenfeld等[32]研究发现在BIM基因正常的ALL细胞中,GC通过介导BIM基因表达上调诱导淋巴细胞凋亡,而BIM基因敲除的ALL细胞则表现出对GC耐药;在泼尼松治疗1周后,GC敏感的ALL患者体内BIM基因表达明显上调,而GC耐药的患者体内BIM基因表达无明显改变。说明BIM基因缺陷或表达受抑与ALL对GC耐药有关。
体外实验发现在GC耐药的ALL细胞中,GC不能介导促凋亡基因BIM表达上调[22, 30],而在BIM基因敲除的小鼠体内,GC诱导的ALL细胞凋亡被抑制[21-22]。进一步研究发现GC能直接或者间接诱导BIM基因表达,同时抑制抗凋亡因子Mcl-1及Bcl-1的活性,促使ALL细胞凋亡[22, 25],以上研究证实GC通过介导BIM基因表达上调诱导ALL细胞凋亡。
4.2 BIM基因表达介导ALL细胞凋亡的作用机制目前认为诱导肿瘤细胞凋亡是肿瘤治疗成败的关键因素。研究发现在正常及恶变的淋巴细胞中,BIM表达产物均能在GC介导的细胞凋亡过程中发挥关键促凋亡作用[26, 28]。Jing等[33]通过动物实验发现在BIM基因内含子区域存在GC受体(glucocorticoid receptor, GR)结合位点,GC通过刺激GR特异性结合这一位点促使BIM基因转录增加,介导白血病细胞的凋亡。Zhao等[31]通过体外实验也证实GC通过与GR结合促进BIM基因表达上调,介导ALL细胞凋亡。研究者还发现GR与BIM协同作用抑制抗凋亡基因Bcl-2及Mcl-1的表达[10, 12, 22, 25, 33],从而说明GC诱导白血病细胞凋亡的过程与GR及BIM协同作用有关。
4.3 BIM基因表达在GC治疗ALL过程中的调节GC在体内通过诱导BIM基因的表达发挥促ALL细胞凋亡作用,然而BIM基因在转录和翻译过程中受多种因素的调节。研究发现,BIM mRNA上有多个miRNA的作用位点,其中miRNA17在转录水平负性调节BIM基因表达[2]。Kfir-Erenfeld等[32]在利用地塞米松诱导淋巴细胞凋亡的过程中发现miRNA-103通过转录和翻译水平促进BIM基因的表达,而miRNA-20a则抑制BIM基因表达。说明BIM基因的表达受多种miRNA共同调节。
GR通过与辅助因子热休克蛋白(heat shock protein, HSP)70和90形成稳定的复合物而存在于细胞质中[8]。既往研究认为HSP90与儿童ALL对GC的耐药性无关[8]。然而Akahane等[24]通过体外实验发现,利用一种高活性的HSP90抑制剂NVP-AUY922处理急性T淋巴细胞白血病(T-ALL)会引起促凋亡蛋白BIM和BAD的表达量增加,同时减少Bcl-2的表达,引起T-ALL细胞的凋亡,从而说明在T-ALL细胞凋亡过程中BIM表达受HSP90负性调节。之所以得出相反的结论,可能与选择的ALL类型、干预措施不同等因素有关。
Heidari等[34]通过对人类白血病细胞进行体外实验,发现转录因子c-jun阴性的白血病细胞能明显减少Bim mRNA的表达和ALL细胞的凋亡,如果恢复c-jun表达则增加GC诱导的BIM基因表达促使ALL细胞凋亡增加,从而说明转录因子c-jun在地塞米松诱导的Bim基因表达过程中发挥重要的调节作用。
5 BIM基因及其表达产物参与的儿童ALL对GC耐药的机制目前研究认为白血病细胞的基因型、临床特点、治疗方案、对药物的反应等因素与ALL的治疗及预后有关。然而,由于受多种因素的共同影响,儿童ALL对GC耐药的相关机制的研究存在困难。
5.1 白细胞介素7受体信号通路中的分子基因突变Li等[1]发现在儿童T-ALL中存在JAK1和KRAS基因突变,这2种基因突变与儿童T-ALL对GC耐药及预后较差有关。JAK1和KRAS基因突变导致其编码的白细胞介素7受体(interleukin 7 receptor, IL7R)信号通路中关键因子缺乏,激活其信号通路下游的AKT和MEK-ERK,引起促生存因子Mcl-1和Bcl-XL表达,抑制BIM基因表达,同时ERK促使BIM蛋白磷酸化而丧失促凋亡活性,最终抑制GC诱导的白血病细胞凋亡[1]。说明JAK1和KRAS基因突变导致GC诱导BIM的表达受抑是ALL对GC耐药的原因之一。
5.2 BIM基因异常Ng等[20]在研究酪氨酸激酶抑制剂耐药的慢性髓细胞白血病时,发现BIM基因内含子2存在长度为2 903 bp的缺失,而这种类型的缺失导致表达的BIM蛋白质缺乏BH3结构域而丧失促凋亡活性。Soh等[35]通过体外实验发现BIM基因内含子缺失与儿童T-ALL对GC耐药有关。Gagné等[5]发现一种BIM基因单核苷酸多态性,C29201T(rs724710)能降低儿童ALL的总体生存率,可能原因是编码的BIM蛋白缺乏BH3结构域导致肿瘤细胞的耐药。说明BIM基因的异常导致其编码的蛋白质结构改变而影响儿童ALL对GC的敏感性。
6 BIM基因在GC耐药ALL治疗中的作用Soh等[35]研究发现通过联合使用其他细胞毒性药物(甲氨蝶呤、长春新碱、左旋门冬酰胺酶等)可以有效克服BIM基因缺失引起的ALL细胞耐药。Korfi等[36]通过体外实验发现,曲美替尼能引起B-ALL中BIM蛋白的去磷酸化及BIM基因表达上调,从而介导白血病细胞的凋亡。通过联合Bcl-2抑制剂AT101和曲美替尼可以促进BIM表达并抑制Mcl-1的促生存作用,最终介导B-ALL细胞的凋亡[6, 36]。Gu等[37]通过对GC耐药的T-ALL进行体外实验研究发现,联合使用雷帕霉素和地塞米松能通过上调Bax及BIM等表达抑制T-ALL细胞的生长,从而说明雷帕霉素和地塞米松协同抑制T-ALL细胞增殖。上述实验说明通过联合化疗的方式可以增加GC诱导的BIM表达,促进ALL细胞凋亡,提高化疗效果。
研究证实,抑制促生存信号通路同样能增加ALL对GC的敏感性。促生存信号通路PI3K/AKT/mTOR被激活可以抑制BIM基因的表达;相反,通过抑制PI3K/AKT/mTOR信号通路可促进BIM基因表达,从而促进肿瘤细胞的凋亡[38-39]。BEZ235是一种PI3K/AKT/mTOR信号通路抑制剂,可以通过抑制AKT1增加BIM的表达同时抑制Mcl-1的表达,最终引起激素耐药的T-ALL对地塞米松的敏感性增加,提升激素介导的白血病细胞凋亡[7, 27]。Liu等[40]通过体外实验发现小剂量(0.1 μmol/L)的茴香霉素联合地塞米松能够促进GC耐药的T-ALL细胞的凋亡,而这一过程是通过活化激素受体及P38-MAPK/JNK信号通路来实现的。Han等[41]研究发现中药槐杞黄能通过抑制AKT/Foxo1及上调BIM基因表达介导ALL细胞的凋亡。所以,通过抑制促生存信号通路中的关键因子可以有效增加ALL细胞内BIM基因的表达,克服ALL对GC的耐药性,促进ALL细胞凋亡。
既然已经证实BIM基因表达产物作为GC诱导ALL细胞凋亡的重要因子[25-28],而抗凋亡因子Bcl-2及Bcl-XL等能够抑制BIM基因表达[21-22, 25],推测使用促生存因子抑制剂可能使GC诱导的BIM基因表达上调引起ALL细胞凋亡。目前口服的Bcl-2及Bcl-XL抑制剂ABT-263是正在进行临床试验的药物,研究表明其能对多种恶性肿瘤发挥抗肿瘤作用[42]。ABT-263通过抑制细胞内抗凋亡因子Bcl-2、Mcl-1及Bcl-XL表达,上调促凋亡BIM的表达,导致肿瘤细胞凋亡[42]。然而复发性ALL对Bcl-2抑制剂耐药的发生率较高,可能与肿瘤复发的过程中白血病细胞生物特性改变有关[42-43],随着新的Bcl-2抑制剂的研发,复发性ALL耐药的问题可能得到有效解决。目前已进入临床试验阶段的还有高选择性的Bcl-2抑制剂ABT199及能广泛抑制Bcl-2、Bcl-XL、Bcl-W的ABT737[44]。随着对Bcl-2基因家族及BH3类似物的研究不断深入,这类药物将来可能成为ALL治疗的新方法。
7 展望BIM基因及其表达产物在GC介导的ALL细胞凋亡过程中发挥重要作用,然而BIM基因在体内的表达受多种因素的影响。因此,通过有效措施促进GC诱导的BIM基因表达,从而增加BIM基因表达产物介导的ALL细胞凋亡可能是今后研究及临床治疗GC耐药的儿童ALL的关键措施之一。
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