急性髓系白血病基因突变及预后研究进展

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[文章编号]1006-2440(2021)03-0235-05
[引文格式]盛烨萍,华海应.急性髓系白血病基因突变及预后研究进展[J ].交通医学,2021,35(3):235-238,242.
急性髓系白血病(acute myeloid leukemia ,AML )是造血干细胞恶性克隆性疾病,具有高度异质性。细胞遗传学和分子生物学异常是其发病的基础,并决定患者的治疗和预后。随着细胞遗传学、分子生物学、二代测序等技术的迅速发展,AML 有关基因的突变成为AML 诊断、危险分层、预后评估及个体治疗的重要指标,NPM 1、FLT 3、C-KIT 、CEBPA 等的临床价值已被证实。近年来,高通量测序技术在
AML 患者中发现更多的基因突变,如TET 2、ASXL 1、IDH 1/IDH 2、DNMT 3A 、RUNX 1、GATA 2等。本文重点介绍近几年在AML 患者中基因突变的频率及预后的研究成果。1
NPM 1
核磷蛋白1(nucleophosmin 1,NPM 1)属于核磷蛋白家族,是一种广泛表达的磷蛋白,能在核仁、核质和胞质之间不断穿梭。该基因位于5q35,包含12个外显子,编码3种核磷蛋白亚型。NPM 1主要有4种功能:(1)参与核糖体生物合成;(2)维持基因的稳定性;(3)依赖p53的应激反应;(4)通过ARF-p53的相互作用从而调控生长抑制途径[1]。
2005年FALINI 等[2]首先发现成人正常核型急性髓系白血病(cytogenetically normal acute myeloid
leukemia ,CN-AML )中NPM 1基因第12号外显子移码突变最频繁。目前已发现该突变约有50余种类
型,其中A 型突变最常见,约占80%,B 型及D 型突变的发生率分别为10%和5%,其他类型罕见[1-2]。NPM 1突变是目前AML 中最常见的基因突变,在成
人AML 中发生率为27%~52%,在CN-AML 中发生率为45%~66%。NPM 1是预后良好的独立因素,2016年WHO 将NPM 1突变列为独特的白血病实体。NMP 1突变且FLT 3-ITD 突变阴性的成人AML
完全缓解率(CR )和总体生存率(OS )偏高,预后趋势较好[3]。STRAUBE 等[4]报道,NPM 1突变伴少量等位基因FLT 3-ITD 患者OS 率较低,复发率(RR )较高。METZELER 等[5]研究发现NPM 1突变患者,特别是FLT 3-ITD 阴性以及CEBPA 双突变时,OS 率较高,
而伴随DNMT 3A 、RUNX 1、ASXL 1等突变患者OS 率明显较低。2
DNMT 3A
DNA 甲基转移酶3A (DNA methyltransferas
3A ,DNMT 3A )基因位于染色体2p23,包含23个外显子,共同编码甲基转移酶。DNMT 3A 能催化胞嘧啶转变为5-甲基胞嘧啶,从而介导启动子区域CpG 岛的超甲基化,调控细胞增殖分化[6]。60%DNMT 3A 突变患者存在甲基转移酶区域R882突变,该突变能抑制甲基转移酶活性,呈显性负调控功能,从而实现低甲基化[7]。
在AML 患者中DNMT 3A 突变率为14%,大部
*[基金项目]国家自然科学基金—青年科学基金项目(81500103);江苏省自然科学基金青年基金(BK20160283)。
**[通信作者]华海应,E-mail:****************
急性髓系白血病基因突变及预后研究进展*
盛烨萍1,2,华海应1**
(1江南大学附属医院,江苏214123;2南通大学医学院)
[摘要]急性髓系白血病(AML )是以原始和幼稚细胞异常增生为特点的恶性克隆性疾病。近年来,随着高通量
测序技术的迅速发展,在AML 中发现越来越多的基因突变,且与患者预后密切相关,对AML 患者的危险分层、个体化治疗、预后判断及靶向治疗具有重要的指导作用。本文就AML 患者中各种基因突变的频率及对预后的影响作一综述。
[关键词]急性髓系白血病;基因突变;突变频率;预后
[中图分类号]R733.71
[文献标志码]B
俄罗斯美女艺术[DOI ]10.19767/jki.32-1412.2021.03.006
算命准吗能信吗·
综述·不可言喻
分是杂合的,在成人CN-AML中突变率22.9%,在M4、M5中常见[8]。DNMT3A在中危患者及CN-AML 中高表达,是预后不良的独立因素。DNMT3A突变同时伴有FLT3和NPM1突变的AML患者无事件生存率(EFS)、OS率较短,RR率较高[9-10]。DNMT3A R882突变患者的OS率及无复发生存率(RFS)低于野生型DNMT3A患者,特别是在伴有NPM1和FLT3-ITD突变的CN-AML患者中,R882突变患者的OS率及无病生存率(DFS)明显降低,是预后较差的分子生物学指标[11]。
弄巧成拙的近义词3FLT3
FMS样酪氨酸激酶3基因(fms-like tyrosine ki-na3,FLT3)属于第Ⅲ类酪氨酸激酶受体(receptor tyrosine kinaⅢ,RTKⅢ)家族成员,位于13q12染色体,编码膜结合蛋白。当配体与FLT3受体在胞外结构域结合后,FLT3二聚体化,从而介导一系列细胞内信号传导,调节细胞分化、增殖和凋亡。FLT3基因突变是AML中常见突变,包括近膜区的内部串联重复(internal tandem duplication,ITD)和酪氨酸激酶结构(tyrosine kina domain,TKD)活化环内的点突变两种形式。在成人AML中FLT3-ITD发生率为20.4%,FLT3-TKD突变发生率为7.7%,可见于FAB 各亚型,其中以M5最多见,M2和M6最少见。THIEDE等[12]发现FLT3突变与野生型FLT3比率大于0.78患者的OS率和DFS率明显较低,低于0.78患者的生存率与FLT3突变阴性患者无明显差异。多变量分析证实,FLT3突变与野生型FLT3比率是独立的预后因素,大于0.4是儿童AML复发的重要独立预后因素[13]。目前关于TKD突变与AML预后的相关性仍有争议,部分研究认为FLT3-TKD突变的长期预后较差[13]。
4IDH
异柠檬酸脱氢酶1和异柠檬酸脱氢酶2(isoci-trate dehydrogena,IDH)参与有氧代谢三羧酸循环,在细胞代谢中发挥着重要作用。IDH基因突变导致蛋白底物结合能力下降,将α-酮戊二酸转化成2-羟基戊二酸(2-HG),竞争性抑制组蛋白去甲基化酶和5-甲基胞嘧啶羟化酶,最终导致DNA超甲基化,造血细胞
增殖分化异常。而2-HG过度积累通过B 细胞淋巴瘤依赖性的诱导及对EgIn家族脯氨酰羟化酶的刺激,导致白血病的发生[14]。
IDH1突变活性部位在氨基酸残基R-132位点,在成人AML突变率为2%~9%,在CN-AML中突变率为10%~15%。而IDH2基因常见突变部位在氨基酸残基R-140或R-172位点,成人AML突变率为5%~14%,在CN-AML中突变率为5%~19%。IDH突变常伴NPM1突变,IDH1突变与IDH2突变在AML中很少共同出现。最近Meta分析显示[15], IDH1突变与较差的CR率、OS率、EFS率有关,且IDH1SNP rs11554137预后也差。而IDH2突变与良好的OS率相关,特别是CN-AML患者R-140及R-172突变的预后良好。
5CEBPA
CCAAT增强子结合蛋白α基因(CCAAT/en-hancer binding proteinα,CEBPA)属亮氨酸拉链转录因子家族,位于19q13,编码长为356个氨基酸残基的蛋白质。CEBPA突变上调节造血干细胞归巢和粒细胞分化的基因,下调参与调控造血细胞增殖的信号分子和转录因子的基因,阻碍DNA从G1期向S期演变,且诱导晚期造血细胞成熟,导致白血病发生。TASKESEN等[16]研究发现CEBPA突变发生率在成人AML中为12.8%,在CN-AML中为5%~14%,双突变比单突变更为常见。CEBPA突变在M1、M2亚型和中危患者中最常见。LI等[17]研究发现CEBPA 双突变患者预后良好,EFS率及OS率显著高于野生
型及单突变患者,单突变与野生型患者预后大致相当。CEBPA单突变易与NPM1、FLT3-ITD、GATA2等突变联合存在。CN-AML伴CEBPA双突变提示预后良好,已纳入NCCN指南,2008年WHO分型也将CEBPA双突变作为预后良好的指标。
6TET2
甲基胞嘧啶双加氧酶2(ten-eleven translocation-2,TET2)属于DNA羟化酶家族成员,包含11个外显子,突变最常发生在第3号外显子和第11号外显子。TET2基因位于AML染色体易位的断裂点4q24上,具有抑癌基因功能,可抑制造血干细胞异常自我更新,阻碍正常造血干细胞分化成熟,导致早晚期造血受阻,引起急性髓白血病和其他髓性增殖性
疾病发生。
TET2突变突变率在AML中为6%~27%,在CN-AML中为6%~36%[18],多见于细胞遗传学中危组,尤其是CN-AML患者。TET2突变能与NPM1、ASXL1等突变伴随,但与IDH1、IDH2突变互斥。目前关于TET2突变的预后研究尚有争议。WANG 等[18]对AML患者生存分析显示,TET2突变者CR 率、EFS率、OS率显著降低,预后较差。GAIDZIK 等[19]研究发现TET2突变与患者的治疗效果、OS率无明显联系,而METZELER等[20]认为在ELN不同分组中,TET2基因突变的预后也不同。CN-AML伴有NPM1和(或)CEBPA阳性且FLT3-ITD突变阴性的患者EFS率、DFS率、CR率及OS率更低。而在CN-AML中
伴有野生型NPM1、CEBPA阳性和(或) FLT3-ITD突变阳性则无明显预后意义。
串串火锅
7C-KIT
C-KIT属于Ⅲ型受体酪氨酸激酶家族,是原癌基因之一,位于染色体4q12-13,共有21个外显子。当C-KIT基因发生突变时,受体会发生自动磷酸化,且不依赖配体也能持续激活下游信号传导通路,最后导致肿瘤的发生。
C-KIT突变在AML中的发生率约为4.2%。AYATOLLAHI等[21]研究发现,C-KIT突变在核心结合因子相关AML(core binding factor-AML,CBF-AML)中发生率为12.8%~46.1%。C-KIT突变患者易复发,特别是D835突变,但对OS率和CR率无明显影响。而YUI等[22]研究发现,D816或同时有D816和N822K突变患者的RFS率及OS率明显低于野生型KIT突变患者。多变量分析显示,D816突变是独立不良预后因素。
8ASXL1
附加性梳样1(additional x combs-like1, ASXL1)位于染色体20q11,包含13个外显子,编码由长约1541个氨基酸组成的核蛋白。ASXL1突变能介导转录稳定蛋白的产生,从而截断C端PHD 域,使其功能缺陷或丧失。
ASXL1突变发病率约为6.1%。PASCHKA等[23]发现ASXL1突变与RUNX1和IDH2(R140)突变相关,而与NPM1、FLT3-ITD和DNMT3A突变呈负相关。与野生型ASXL1患者相比,ASXL1突变患者的CR率、EFS率和OS率较低。在多变量分析中,ASXL1和RUNX1突变作为单一变量对预后无显著影响,但突变基因之间有显著相互作用,特别是ASXL1突变伴RUNX1突变的AML患者有极高的死亡风险。
9RUNX1
Runt相关转录因子1基因(Runt-related tran-scription factor1,RUNX1)位于21q22染色体,编码转录核心结合因子。
SOOD等[24]研究显示,RUNX1突变发生率在儿童AML为3%,在成人AML为15%。RUNX1突变经常伴随FLT3-ITD、FLT3-TKD和MLL-PTD突变,而与NPM1突变相互排斥。GAIDZIK等[25]对2 439例AML患者进行研究,发现RUNX1突变率为10%,与野生型RUNX1相比,RUNX1突变与年龄较大、男性、更不成熟的形态及继发性AML(由骨髓增生异常综合征演变而来)有关。RUNX1突变的预后因共突变的伴侣基因而异,伴随ASXL1、SRSF2、PHF6突变患者的预后明显较差,而伴IDH2突变患者预后较好。
10GATA2
GATA结合蛋白2(GATA-binding protein2, GATA2)属于转录因子家族成员,位于染色体3q21,编码由474个氨基酸组成的转录因子,具有锌指结构,参与造血过程中髓系转化。
GATA2突变在所有AML患者中发生率为9.9%,在CEBPA双突变队列中突变率为18.3%,在野生型CEBPA队列中突变率为3.3%[26]。HOU等[27]发现GATA2突变患者OS率和RFS率明显高于GATA2突变阴性患者,GATA2突变的AML患者预后良好。
综上所述,基因突变与AML预后密切相关,如NPM1且FLT3突变阴性,CEBPA双突变较常见,且已有明确的临床证据证明其预后良好。IDH2、GATA2突变相对少见,同样提示预后良好。FLT3-ITD、DNMT3A、CEBPA单突变、IDH1、RUNX1发生率较高,预后较差;ASXL1、C-KIT、TET2发病率相对较低,同样提示预后差。
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[收稿日期]2020-07-27
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[收稿日期]2021-01-04

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