（1福建医科大学协和临床医学院 福建 福州 350000）
（2福建省建新医院检验科 福建 福州 350000）
【摘要】 骨髓增生异常综合征是一组临床异质性疾病，本病最主要的两个特征是骨髓病态造血导致外周血细胞一系或多系减少和高风险向白血病转化。异柠檬酸脱氢酶基因突变可导致其正常产物α-酮戊二酸大量转变为D-2-羟基戊二酸，从而导致α-酮戊二酸依赖性酶活性不足，进一步影响基因组的表观遗传学修饰。骨髓增生异常综合征中携带异柠檬酸脱氢酶基因突变的低危组患者往往总生存期较短。该基因突变在病程中较为稳定，并不影响患者向白血病转化。
【关键词】骨髓增生异常综合征；异柠檬酸脱氢酶基因突变；预后；白血病
【中图分类号】R551.3 【文献标识码】A 【文章编号】2095-1752（2017）08-0007-04
The Research On the Relation Between Mutation of Isocitrate Dehydrogenase And the Prognosis of Myelodysplastic Syndrome
Huang Zhongyang1,2;Chen Yuan2.
1Union Clinical Medical College,Fujian Medical University;2Department of Clinical Laboratory, Fujian Provincial Jianxin Hospital
【Abstract】Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell disorders. They are characterized by two cardinal featuers: ineffective hematopoiesis leading to blood cytopenia and an increased risk of developing acute myeloid leukemia (AML). Mutants of isocitrate dehydrogenase (IDH) can no longer catalyze isocitrate to α-ketoglutarate (α-KG) and, instead, reduce α-KG to D-stereoisomer of 2-hydroxyglutarate (D-2-HG), which competitively inhibit α-KG-dependent enzymes and influence the epigenetic modification of genome. Patients who are in lower-risk group with mutation-positive IDH have a shortor overal survival (OS) than wild-type. The mutations of IDH remain stable during MDS evolution and have little role in the progression to AML.
【Key words】Myelodysplastic syndrome; Mutants of isocitrate dehydrogenase; Prognosis; Acute myeloid leukemia
骨髓增生异常综合征（MDS）系以一系或多系外周血血细胞减少、骨髓无效造血并高风险向急性白血病转化为特征的一组异质性疾病[1、2]。根据2008年世界卫生组织（WHO）[3]，该综合征可分为以下若干亚型：单系病态造血的难治性血细胞减少（refractory cytopenia with unilineage dysplasia，RCUD）、环状铁粒幼细胞性难治性贫血（refractory anemia with ringed sideroblast，RARS）、难治性血细胞减少伴多系病态造血（refractory cytopenia with multilineage dysplasia，RCMD）、难治性贫血伴原始细胞增多-1/2（refractory anemia with excess blast，REAB-1/2）、5q－综合征、不能分类的MDS（MDS-U）。目前对MDS的预后评分系统主要根据患者的核型以及临床情况，如血细胞减少程度、骨髓原始细胞数量等。尽管现有的预后评分系统如国际预后积分系统（International Prognostic Scoring System，IPSS）[4]、改良IPSS（R-IPSS）[5]、WHO分型预后积分系统（WHO-classification-based Prognostic Scoring System，WPSS）[6]在很大程度上帮助患者评估预后和指导治疗，但仍有许多影响预后的因素，特别是新发现的一些分子生物学标记，如TET2[7、8]、ASXL1[9、10]。今就最近在MDS中发现的异柠檬酸脱氢酶（isocitrate dehydrogenase，IDH）基因突变及其对MDS预后的影响作一综述。
1.IDH1/2基因及其编码的蛋白结构和功能
哺乳动物细胞中存在3种IDH：IDH1～3[11]。IDH1和IDH2是结构相似的同工异构酶，而IDH3与前二者不同，其结构是一个包含2个α亚基、1个β亚基和1个γ亚基的异源四聚体蛋白，且迄今为止尚未有任何IDH3基因与肿瘤的相关报道。人类IDH1基因定位于染色体2q33.3，全长18854个核苷酸，其mRNA长度为2339bp，包含10个外显子，仅有一种剪接方式，其编码的IDH1蛋白有414个氨基酸残基，存在于细胞胞浆和过氧化物酶体中[12、13]。IDH2基因定位于染色体15q26.1，全长18499个核苷酸，其mRNA长度为1740bp，包含11个外显子，也仅有一种剪接方式，其编码的IDH2蛋白有452个氨基酸残基，存在于线粒体中[14]。IDH1/2以同源二聚体的形式存在，是一类非常重要的代谢酶，二者以烟酰胺腺嘌呤二核苷酸（NAD+）或烟酰胺腺嘌呤二核苷酸磷酸（NADP+）为辅酶，催化异柠檬酸氧化脱羧生成α-酮戊二酸（α-ketoglutarate，α-KG），同时生成还原型烟酰胺腺嘌呤二核苷酸（NADH）和还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH）[15]。
2.IDH1/2基因突变与MDS的关系
IDH基因突变最初是2006年在转移性结肠癌中被报道[16]，2008年发现约12%的多形性胶质母细胞瘤患者存在IDH1基因的R132点突变[17]。2009年，全基因组测序在一位急性髓系白血病患者中也发现IDH1基因的R132点突变[18]。随后在多中心对大量急性髓系白血病患者进行分析证实了IDH1基因的R132点突变的存在，同时发现IDH2基因的R140和R172的点突变[18-27]。而素有前白血病（pre-leukemia）之称的MDS同样存在IDH1/2基因的突变，只不过频率比急性髓系白血病低得多[20、26、28]。
2.1 IDH1基因突变类型
IDH1基因突变基本表现为点突变导致的氨基酸置换，常见的为肽链第132位点上精氨酸（IDH1R132）被不同的氨基酸取代，如395G→A导致R132H（组氨酸，H）；394C→A导致R132S（丝氨酸，S）；394C→T导致R132C（半胱氨酸，C）；394C→G导致R132G（甘氨酸，G）；395G→T导致R132L（亮氨酸，L），其中以R132H和R132C最常见[29]。当然，也有罕见突变报道，如368C→A导致R123E（谷氨酸，E）；297A→G导致R99M（蛋氨酸，M）；379C→T和381T→C的联合点突变导致R127S（丝氨酸，S）；388A→G导致R130V（缬氨酸，V）。
2.2 IDH2基因突变类型
IDH2基因的突变类型也是以点突变导致的氨基酸置换，常见的为肽链第140位点上精氨酸（IDH2R140）被不同的氨基酸取代，如419G→A导致R140Q（谷氨酰胺，Q）最常见[29]，可占IDH2基因突变的95%，其次为418C→T导致R140W（色氨酸，W）。IDH2R172突变相对少见，绝大多数为515G→A导致R172K（赖氨酸，K），极少数为515G→T导致R172M（甲硫氨酸，M）。
2.3 IDH1/2基因突变后的致瘤机制
绝大多数肿瘤相关的酶基因突变会导致其编码的蛋白质功能失活或异常激活，这种特征也存在于发生IDH基因突变的MDS患者中。研究发现，IDH1和IDH2两种突变均可导致其对底物的亲和力降低，并更易同α-KG及NADPH结合，结果使α-KG转化为具有立体异构的D-2-羟基戊二酸（D-stereoisomer of 2-hydroxyglutarate，D-2-HG），并使NADPH转化成NADP+。也有研究报道，在胶质瘤和急性髓系白血病患者中，携带IDH1/2突变者的D-2-HG水平较野生型高出100倍[23、30-32]。
目前关于2-羟基戊二酸（2-hydroxyglutarate，2-HG）的代谢去路还不完全清楚，其有两种旋光异构体，左旋2-羟基戊二酸的病理性累积可见于一种少见的常染色体隐性遗传性疾病，常伴有脑病和脑肿瘤的高发风险[33]。而IDH1/2基因突变者会产生高水平的D-2-HG而非左旋2-羟基戊二酸，且高水平的D-2-HG可能存在潜在的致肿瘤作用[34]。
首先，高水平的D-2-HG可通过提高活性氧簇（reactive oxygen species，ROS）介导DNA损伤[32、35]。其次，D-2-HG还可通过损伤线粒体呼吸链诱发氧化应激。更为重要的是，D-2-HG和α-KG的化学结构极为相似（仅第2位碳原子上D-2-HG由α-KG的氧原子变为羟基），故D-2-HG可竞争性抑制α-KG依赖的相关酶类，例如脯氨酸羟化酶（prolyl hydroxylase，PHD）、组蛋白赖氨酸去甲基酶、5-甲基胞嘧啶羟化酶。
2.3.1影响低氧诱导因子-1α的稳定性 低氧诱导因子-1α（hypoxia-inducible factor 1α，HIF-1α）系一种转录因子，与血管生成和肿瘤发生有关。在非缺氧情况下，PHD介导的泛素化降解下调其蛋白水平[36]。在IDH1/2基因突变的肿瘤细胞中由于α-KG水平下降，PHD活性受到抑制，最终将影响HIF-1α的稳定性[35]。
2.3.2影响染色质修饰 TET癌基因家族成员-2（TET-2）参与DNA去甲基化过程中5-甲基胞嘧啶的羟化，这一过程需要α-KG的参与[37]。在IDH1/2基因突变的肿瘤细胞中由于α-KG水平下降，抑制TET-2介导的5-甲基胞嘧啶羟化，从而导致DNA处于高度甲基化状态。许多高度甲基化的基因中含有GATA1/GATA2和EVI1等转录因子结合位点，正常情况下在髓系分化和白血病形成中均有重要作用，其高度甲基化势必导致髓系分化阻滞和恶性克隆形成。
组蛋白赖氨酸去甲基酶亦是α-KG依赖性酶。体外研究证实D-2-HG可抑制组蛋白脱甲基[38、39]。而甲基化的组蛋白，如H3K9me3（trimethylation of lysine9 of histone H3）能募集组蛋白甲基转移酶和DNA甲基转移酶，进一步促进组蛋白和DNA的甲基化，进而影响髓系分化[40、41]。
3.IDH1/2基因突变的MDS临床特征
IDH1/2基因突变频率在MDS患者中的检出因种族、患者的选择偏倚而不同，在3.5%～12%之间不等[28、42-45]。一般而言，IDH2基因的突变频率要高于IDH1。Bejar等报道IDH1和IDH2基因的突变频率分别为1.4%和2.1%[42]；Kosmider等报道的突变频率分别为2.0%和3.0%[43]；而Patnaik等报道的突变频率要比之前两项研究高，IDH1和IDH2基因突变频率分别达2.9%和9.4%[44]。此外，IDH基因的突变率也因MDS的亚型不同而有差异，在FAB分型中，以难治性贫血伴原始细胞增多-转化型（refractory anemia with excess blast-transformation，RAEB-t）和慢性粒-单核细胞白血病（chronic myelomonocytic leukemia，CMML）为高，而在RA、RARS、RAEB亚型中发生率基本和之前学者报导的一致。RAEB-t由于骨髓原始细胞比例较高，WHO分型已将其归为急性髓系白血病，二者IDH基因突变频率相近[46、47]。同样，WHO分型业已将CMML从MDS中剔除。
3.1 临床表现
同野生型相比，IDH基因突变患者在初诊时年龄往往偏大，血小板计数偏高（P＜0.05）。而在其他临床参数、WHO分型、IPSS、R-IPSS、染色体核型方面突变型和野生型无明显差异。当仅考虑IDH2基因突变时，则得到同样的结果。
3.2 与其他常见的突变基因伴随关系
同野生型相比，IDH基因突变患者往往合并至少一种额外的分子生物学异常，其中ASXL1基因、DNMT3A基因、SRSF2基因的突变频率明显较野生型高（P＜0.05）。当分别分析IDH1和IDH2基因时，则仅IDH2基因突变患者合并上述三个基因突变的频率明显较野生型高（P＜0.05）。
3.3 IDH1/2基因突变的稳定性
在MDS病程进展中，IDH基因突变是相当稳定的[46、48]。Thol等曾报道1例MDS患者在进展为急性髓系白血病时仍保留原先IDH1的突变[28]。Lin等报道9例携带IDH基因突变的MDS患者有7例保持原突变，2例在化疗取得缓解后突变丢失。而142例诊断时IDH基因为野生型患者在疾病进展时仅1例获得新的突变[47]。上述报道说明在部分患者中，IDH基因突变可能参与MDS疾病的发生，但在病情进展和演变上几乎没有作用。
4.伴IDH1/2基因突变的MDS患者预后
IDH基因突变在MDS患者中的预后意义目前尚未明确。Jin[49]等研究发现，携带IDH1/2基因突变患者的总生存期（overall survival，OS）明显短于野生型，而进一步分层分析发现，IDH1/2基因突变仅对IPSS评分为中危-1组患者的OS有不利影响。当分别分析IDH1和IDH2突变基因时，则仅IDH1基因突变对OS有不利影响。同时，IDH1/2基因突变对无白血病生存期（leukemia free survival，LFS）无影响，亦提示该突变在病情进展和演变上几乎没有作用。Thol[28]等单因素分析发现，携带IDH1基因突变患者较野生型有着较短的OS和较低的无事件生存率（event free survival，EFS）。进一步多因素分析提示，IDH1基因突变是对OS和EFS独立的预后不良因素。Lin[47]等研究发现，携带IDH2基因突变的患者的OS明显短于野生型。分层研究发现，IDH基因突变仅对IPSS分组下的低危和中危-1组、FAB分型下的RA、RAS亚型、R-IPSS分组下的极低危和低危组的OS有影响。而多因素分析并不提示IDH基因突变是OS的独立预后不良因素。
综上所述，IDH基因突变是低危MDS患者独立预后不良的因素之一，该基因突变与否甚至可参与低危MDS患者的进一步危险分级、早期复发的监测等。
5.IDH1/2基因突变与ALL和MPN
IDH基因在急性淋巴细胞白血病（acute lymphoblastic leukemia，ALL）患者中的突变率一般较低。Kang[50]等报道突变率为1.7%（1/60），Abbas[51]等报道的为1%（1/96），而Andersson[52]等在一个288例儿童ALL样本中仅检测出1例IDH基因突变。而且携带该突变基因者以正常核型居多，往往异常表达髓系抗原，如CD13、CD33等，且预后欠佳。Zhang[53]等发现的3例携带IDH突变基因的ALL患者，有2例为正常核型并表达髓系抗原。但无一例外，这3例患者均在6个月内复发或死亡。
骨髓增殖性肿瘤（myeloproliferative neoplasms，MPNs）系一组克隆性造血干细胞疾病，表现为髓系（粒系、红系、巨核系）细胞一系或多系增殖，WHO[3]将其分为以下8类：慢性粒细胞白血病，BCR-ABL1阳性、慢性中性粒细胞白血病、慢性嗜酸性粒细胞白血病，非特指型、真性红细胞增多症、原发性血小板增多症、原发性骨髓纤维化、肥大细胞增生症、骨髓增殖性肿瘤，未分类。一般而言，在MPNs病程的慢性期IDH基因突变的检出率较低，而在急变期则较高。Pardanani[54]等在一个200例慢性期或急变期的MPNs样本中共检出5例IDH1和4例IDH2基因突变，其中急变期和原发性骨髓纤维化IDH基因突变检出率分别为21%和4%，未在真性红细胞增多症和原发性血小板增多症检出。Abdel- Wahab[55]等研究发现，IDH1基因突变率在原发性急性髓系白血病、继发于MDS的急性髓系白血病、继发于MPNs的急性髓系白血病中无统计学差异。
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论文作者:黄忠杨 陈源
论文发表刊物:《医药前沿》2017年3月第8期
论文发表时间:2017/3/30
标签：基因突变论文; 突变论文; 基因论文; 患者论文; 白血病论文; 骨髓论文; 细胞论文; 《医药前沿》2017年3月第8期论文;