临床医学进展  >> Vol. 10 No. 5 (May 2020)

融合基因在儿童急性淋巴细胞白血病中的临床意义
The Clinical Significance of Fusion Gene in Childhood with Acute Lymphoblastic Leukemia

DOI: 10.12677/ACM.2020.105123, PDF, HTML, XML, 下载: 63  浏览: 229 

作者: 康 慧:山西医科大学儿科医学系,山西 太原;郝国平*:山西省儿童医院血液科,山西 太原

关键词: 急性淋巴细胞白血病融合基因儿童Acute Lymphoblastic Leukemia Fusion Gene Children

摘要: 急性淋巴细胞白血病是最常见的儿童血液肿瘤,由于分层诊疗、免疫治疗以及骨髓移植等方法的应用,儿童急性淋巴细胞白血病的生存率明显增高。融合基因是儿童急性白血病常见的遗传学异常,其在急性白血病的发生发展、诊疗预后等方面有重要意义。本文总结了儿童急性淋巴细胞白血病中出现的部分融合基因,就其在儿童急性淋巴细胞白血病的发生发展、辅助诊断、指导治疗、疗效评估、预后预测等方面的临床意义进行综述。
Abstract: Acute lymphoblastic leukemia is the most common malignant tumor of children's blood system. Because of the application of stratified diagnosis and treatment, immunotherapy and bone marrow transplantation, the survival rate of children with acute lymphoblastic leukemia has significantly increased. Fusion gene is the common genetic abnormality in childhood with acute leukemia, which is of great significance in the occurrence, development, diagnosis, treatment and prognosis of acute leukemia. This report summarizes some fusion genes in childhood with acute lymphoblastic leukemia, and summarizes their clinical significance in the occurrence and development, assistant diagnosis, guiding treatment, efficacy evaluation and prognosis prediction of children with acute lymphoblastic leukemia.

文章引用: 康慧, 郝国平. 融合基因在儿童急性淋巴细胞白血病中的临床意义[J]. 临床医学进展, 2020, 10(5): 801-810. https://doi.org/10.12677/ACM.2020.105123

1. 引言

急性淋巴细胞白血病(acute lymphoblastic leukemia, ALL)是一种以骨髓、外周血和组织器官中幼稚淋巴细胞增殖为特征的异质性血液病。在美国,经年龄调整的ALL每年发病率是1.38/10万人 [1],在2019年,大约有5930例新发患者,1500例死亡患者 [2]。儿童ALL是最常见的儿童血液肿瘤,占儿童急性白血病(acute leukemia, AL)的75%~80% [3],包括急性B系淋巴细胞白血病(B-cell acute lymphoblastic leukemia, B-ALL)和急性T系淋巴细胞白血病(T-cell acute lymphoblastic leukemia, T-ALL)。近年来,随着当前危险度分层诊疗方案、新型非化疗药物以及免疫治疗的应用,儿童ALL的治愈率及生存率已经显著提高。根据监测、流行病学和预后(Surveillance, Epidemiology, and End Results, SEER)数据显示ALL儿童5年总生存率(overall survival, OS)为89% [4]。

融合基因(fusion gene)由染色体易位、重排等形成,是遗传和环境因素共同作用的结果。不同种族融合基因的发生频率不同。危地马拉TEL-AML1融合基因的发病率(4.5%)与西班牙(2%)和印度等国家的发病率(4.8%~9%)一致 [5]。目前已经检测出许多ALL相关融合基因,其在白血病的发病机制、诊断确定、疗效评估、预后预测及治疗指导方面发挥着重要的作用,也是微小残留病变(Minimal residual disease, MRD)监测的重要依据。现对儿童ALL的部分融合基因进行综述。

2. TEL (ETV6)相关融合基因

TEL (ETV6)基因位于12p13,属于红细胞转化特异性家族,是造血过程中重要的转录抑制因子,参与重排、局灶性缺失和序列突变,已经发现在ALL中与TEL基因融合的伙伴基因有AML1 (RUNX1)、ABL1、ABL2、ARNT、PAX5、TTL、STL、NCOA2、BAZ2A、IGH、NTRK3、AIF1L、EIF4B、SNUPN、NUFIP1等。

(一) TEL-AML1 (ETV6-RUNX1)融合基因

由t (12; 21) (p13; q22)易位形成的TEL-AML1融合基因最早在1995年被报道 [6]。TEL-AML1融合基因阳性者几乎均为B-ALL,是儿童最常见的融合基因,我国报道TEL-AML1融合基因的发生率为20%~25%,在儿童中的阳性率(18.89%)高于成人(1.06%) [7] [8]。有许多国家报告了该基因的高发病率,包括英国(39%)、澳大利亚(33%)、美国(17%)、德国(18.9%)、意大利(18.9%)和巴西(17.9%) [9]。目前普遍认为TEL-AML1融合基因促进白血病形成的机制是“双打击模型” [10] [11],即在出生前,TEL基因与AML1基因融合导致正常细胞转化成恶性细胞,然后持续克隆,产生继发性的遗传异常,如der(5) (q31.3)、der(5) (q33.3)等,达到一定数量的拷贝数改变(copy number alteration, CAN)后,导致白血病形成。Adrián Montaño等 [12] 通过建立体外ETV6-RUNX1基因敲除模型总结出ETV6-RUNX1融合蛋白在维持白血病表型中起重要作用,可能成为潜在的治疗靶点。

TEL-AML1融合基因的预后意义仍在争论中。Yu Wang等 [13] 研究了77例TEL-AML1融合基因阳性患儿的临床特点和治疗结果,第33天所有患儿达到了完全缓解(CR),5年OS率高(97% ± 2%),累计复发率为低(2.1%),晚期复发(42月),预后良好。M. Ampatzidou等 [14] 单因素分析显示TEL-AML1融合基因阳性与良好预后和OS率相关,但在多因素分析中,TEL-AML1融合基因不具有独立的预后意义。TEL-AML1融合基因表达水平在诱导化疗后与移植后有重要的预后价值,也可作为MRD的标志。研究表明,TEL-AML1融合基因阳性ALL患儿尽管接受了异基因造血干细胞移植(allogeneic hematopoietic stem cell transplantation, allo-HSCT),仍有20%病例复发 [12],复发机制仍在研究中,可能与CNA相关,需要研究更多关于TEL-AML1融合基因阳性ALL患儿CNA。

(二) TEL-ABL1融合基因

TEL-ABL1融合基因在淋巴和髓系白血病中均可存在,二者融合不能从简单染色体易位导致。在大多数情况下,二者融合是通过将ABL1基因的倒置部分插入到第十二号染色体上的ETV6基因或将ETV6的倒置部分插入到第九染色体上的ABL1而产生的,可能涉及更复杂的染色体重排。Lukes等 [15] 报道了一例ETV6-ABL1阳性BCP-ALL儿童患者,其染色体重排不仅产生了ETV6-ABL1融合,而且还产生了两个额外的框内基因融合:AIF1L-ETV6和ABL1-AIF1L。AIF1L的生物学作用还不清楚,这两个融合基因的临床意义尚待阐明。

TEL-ABL1融合基因不常见,在儿童ALL中的发生率极低(0.17%) [16]。据报道80% TEL-ABL融合基因阳性患者同时有CDKN2A/B和IKZF1缺失,超过60%患者死亡,预后不良 [16] [17]。酪氨酸激酶抑制剂(tyrosine kinase inhibitor, TKI)可特异性抑制TEL-ABL1酪氨酸激酶的活性,因而是治疗TEL-ABL1融合基因阳性患儿的重要方法,但是,该融合基因阳性肿瘤潜在的TKI抵抗机制尚在研究中。通过建立一个长期予以伊马替尼的TKI耐药的TEL-ABL1融合基因阳性白血病细胞系,发现GNB1K89M获得性突变与TKI抵抗机制有关 [18]。

(三) ETV6-SNUPN、ETV6-NUFIP1、ETV6-EIF4B融合基因

Mata-Rocha等 [19] 首先在一例高危B-ALL儿童中同时发现ETV6-SNUPN和ETV6-NUFIP1融合基因,并指出该患儿病情进展迅速,对化疗反应差,在2周后死亡。这可能意味着这两种融合基因阳性患儿预后不良,但需考虑该患儿本身存在高风险危险因素。

ETV6-EIF4B融合基因是一种新型融合基因,Kim等 [20] 运用二代测序(next-generation sequencing, NGS)首次在B-ALL儿童中发现,ETV6的DNA结合结构域被EIF4B的RNA和eIF4A结合结构域取代。但是,二者融合的预后尚不明确,需收集更多该融合基因阳性的病例进一步研究。

(四) TEL-NTRK3融合基因

TEL-NTRK3融合基因罕见,在ALL中发生率很低,儿童中尚未报道。NTRK3基因编码原肌球蛋白受体酪氨酸激酶(TRK)家族成员TRKC,因此,特异性TRK抑制剂可能是治疗TEL-NTRK3融合基因AL患者的有效方法。Roberts等 [21] 用基因工程小鼠模型证实了TEL-NTRK3在白血病发展中的作用,并报告了TRK抑制剂的显著效果,目前有几种TRK靶向药物正在临床开发中,包括entrectinib和larotrectinib [22]。

3. 混合谱系白血病融合基因

混合谱系白血病(mixed lineage leukemia, MLL)基因,也称KMT2A,HRX,ALL1,位于染色体11q23,参与AL亚型的染色体易位,约占ALL的10% [23]。该基因与多种易位伙伴基因(translocation partner gene, TPG)融合,迄今为止,共鉴定出135种不同的MLL重排,其中94种TPG在分子水平上已被鉴定,其中有84个是直接TPG,即该基因在框架结构内形成MLL融合蛋白。94个TPG中有35个反复发生,但只有9个特异性基因融合占所有MLL基因重排的90%以上 [24]:AF4 (AFF1)、AF6 (MLLT4)、AF9 (MLLT3)、AF10 (MLLT10)、ELL、ENL (MLLT1)、EPS15 (AF1P)、PTD、AF1Q (MLLT11)。欧洲一项研究中指出,在0~18岁儿童ALL中,MLL相关融合基因最常见的依次是MLL-AF4 (47.4%)、MLL-AF9 (16.8%)、MLL-ENL (20.9%)、MLL-AF10 (5.0%)、EPS15 (2.2%)、MLL-AF6 (1.7%) [24]。

MLL融合基因与年龄、性别相关。MLL-AF4在婴儿和成人的发病率较儿童高,MLL-ENL在婴儿和儿童的发病率较成人高,AF10在儿童发生率高,PTD更倾向儿童和成人。MLL-AF10 (P = 0.0024)在男性患者组中出现的频率更高,而女性患者受MLL-AF4融合的影响更大(P = 0.00576) [24]。这与MLL断点定位有关。ALL和年轻患者通常表现为MLL内含子11断裂,而急性髓细胞白血病(acute myelogenous leukemia, AML)和老年患者MLL内含子9断裂较多。

目前,长距离运作反向PCR (long-distance inverse PCR, LDI-PCR)技术可以鉴定直接和互惠的MLL融合、MLL基因内部复制、11号染色体倒位、11号染色体缺失和11号染色体插入其他染色体,或其他染色体插入MLL基因,没有其他技术(如NGS)显示出如此高的染色体融合位点识别率。基于PCR技术以及MLL融合等位基因在遗传上是稳定的,可以建立特定的染色体融合位点的特异性PCR引物,用于MRD的监测,将有助于白血病患者更好的分层,进一步改善预后。但是对于婴儿患者,由于潜在的IG/TR-MRD-PCR靶点相对较少,MLL融合DNA重排的有效性对MRD监测的临床应用有很大的影响,需要进一步研究。

世界卫生组织(WHO)将MLL白血病分为AML、B-ALL和一个不明确谱系的急性白血病 [25]。与非MLL白血病相比,MLL白血病具有突发性、侵袭性进展和不良预后。我国2018年儿童ALL急性淋巴细胞白血病诊疗规范将MLL基因重排阳性作为高危组因素,美国国家综合癌症网络(National Comprehensive Cancer Network, NCCN)临床实践指南:儿童急性淋巴细胞白血病(2020.V2)中将MLL基因重排列为不利危险因素。关于MLL白血病治疗,根据风险分层采用诱导联合化疗的治疗可达到90%的患者完全缓解,但随后复发率很高,这一趋势已在一些研究中报道 [26] [27]。MLL白血病患儿的5年EFS率(20%~40%)明显低于非MLL白血病患儿(60%~80%) [27]。尽管诱导治疗获得了极好的CR率(80%~90%),但MLL白血病婴儿患者容易复发,二次缓解失败,总体生存率低 [26]。其他治疗,包括核苷类似物低甲基化剂,如去甲脒、氮胞苷和氯法拉滨、地西他滨,组蛋白甲基转移酶(DOT1L)抑制剂,组蛋白去乙酰化酶(HDAC)抑制剂,如vorinostat和romidepsin、panobinostat,也具有临床意义,需要进一步的临床实验研究。还有Fms样受体酪氨酸激酶-3 (FLT-3)抑制剂,如lestaurtinib和quizartinib,对儿童MLL重排阳性白血病预后仍有争议 [28] - [33]。嵌合抗原受体T细胞(Chimeric antigen receptor T cell, CAR-T)治疗通过免疫表型和细胞遗传学技术确定每个患者的关键靶点,为MLL白血病患者个体化用药提供了机会。Gardner等 [34] 治疗了7例MLL基因阳性B-ALL,所有患者经CD19 CAR-T细胞治疗后骨髓均获得CR,但在输注CAR-T细胞后1个月内,2例患者发生了与B-ALL密切相关的AML,这是CD19阴性免疫逃逸的新机制,这对接受CD19 CAR-T细胞治疗的复发难治性MLL重排阳性B-ALL患者的治疗具有指导意义。但是,由于这种治疗方法的新颖性以及收集到的病例少,长期EFS、OS率仍然不确定。更多涉及MLL白血病患者的研究将有助于利用CAR-T或其他靶向药物对这种难治AL亚组进行更有效的治疗。

4. BCR-ABL1融合基因

BCR-ABL1融合基因由t (9; 22) (q34; q11)易位形成,也称费城染色体(Ph染色体),见于90%慢性髓系白血病和25%ALL以及大约5%AML [35]。根据BCR基因断裂位点的不同,可分为三种亚型:p210 [(b2a2 (e13a2)或b3a2 (e14a2)],p190 (e1a2),p230 (c3a2),以前两者最为常见;此外,应用原为荧光杂交技术(fluorescence in situ hybridization, FISH)发现BCR-ABL e14a3 [36]。

WHO 2016年ALL分类中,将伴有BCR-ABL1阳性ALL单独作为一类,并认识到TKI治疗有效 [25]。国家综合癌症网络(NCCN)将BCR-ABL1融合基因阳性患者分类为低风险组。我国2018年儿童ALL诊疗规范将BCR-ABL1融合基因作为预后不良的危险因素,由于TKI靶向治疗的应用,已使该因素从高危风险组降到中危风险组,临床中,更注重TKI药物治疗,而不是增强化疗强度。目前,应用TKI靶向联合化疗已使BCR-ABL1融合基因阳性患儿5年EFS率达70%~80% [37],但复发和耐药性仍然是临床医生面临的巨大挑战。Zhanglin Zhang等 [35] 用FISH在52例ALL患者中观察到12个BCR-ABL1信号,包括1R1G2F、1R1G1F、2R1G1F、1R2G1F、2R2G1F、2R2G1F、1R2G2F、1R1G3F、1G3F、2G3F、1G4F、1R1G4F和1R4F,得出与伴有单一BCR-ABL1信号患者(15个月)相比,具有复杂信号患者OS时间较差(5个月) (P = 0.006)。因此,利用FISH监测BCR-ABL1信号可能为这些患者提供预后指导和治疗选择。

5. TCF3 (E2A)相关融合基因

TCF3 (E2A)基因位于19p13.3,该基因重排在儿童B-ALL中较常见,约占6% [38]。迄今为止,已经检测到TCF3融合基因伙伴有PBX1、HLF、ZNF384、FLI1、TEF,分别导致了t(1; 19)、t(17; 19)、t(12; 19)、t(11; 19)、t(19; 22)的易位,由于患儿预后与TCF3基因的融合伙伴相关,因此,检测并识别各类伙伴基因及其特征相当重要。配对测序(Mate-pair sequencing, MPseq)基于NGS,能够检测到隐秘的染色体重排,有助于全面了解基因组结构变异。

(一) TCF3-PBX1融合基因

PBX1 (1q23)基因是TCF3最常见的易位伙伴,导致TCF3-PBX1基因融合,目前被WHO列为B-ALL复发性遗传异常 [39],被我国2018年儿童ALL诊疗规范列为中危组危险因素。我国有研究报道,TCF3-PBX1基因融合阳性患儿5年EFS率、OS率分别是84.4% ± 15.6%、86.0% ± 17.6% [40],基因表达持续阳性者行allo-HSCT可提高疗效,减少复发 [41],TCF3-PBX1表达水平高于0.31%可表明移植后容易复发 [42],可用于评估allo-HSCT后MRD状态,及早检测,可为干预和治疗策略提供新的视角。

(二) TCF3-HLF融合基因

HLF (17q22)基因儿童ALL预后差的指标,二者融合形成的TCF3-HLF融合基因被我国2018年儿童ALL诊疗规范列为高危组危险因素。已有研究发现该融合基因致白血病发生机制 [43],携带TCF3-HLF融合基因患儿经治疗后可获得形态学缓解,但病情进展迅速,即使行HSCT也生存期短,预后差 [44]。而TEF基因由于与HLF功能相似,可能代表预后差,需要对TCF3-TEF融合基因患儿进一步随访 [38]。

6. ZNF384相关融合基因

ZNF384基因位于12p13.31,迄今为止,已经发现了8个伙伴基因,包括EP300、TCF3、TAF15、CREBBP、BMP2K、EWSR1、SYNRG、ARID1B。由于ZNF384相关融合基因阳性患儿病例少以及新伙伴基因的出现,因此,不同研究中ZNF384相关融合基因发生率不同。Hirabayashi等 [45] 研究显示ZNF384相关融合基因在儿童B细胞前体ALL (B-cell precursor acute lymphoblastic leukemia, BCP-ALL)中发生率为4.1%,而Shago等 [46] 则总结出儿童B-ALL ZNF384相关融合基因发生率为3.0%,但是不同ZNF384相关融合基因发生率尚不明确。

携带ZNF384相关融合基因BCP-ALL患儿,具有特征性免疫表型,都表现出CD10迟钝或阴性表达,并且大部分表达CD13和(或) CD33。该类患者临床特征和预后结果取决于ZNF384伙伴基因。其中,EP300-ZNF384融合基因阳性患者发病年龄相对较大,白细胞计数无明显增高,对泼尼松反应良好,对常规化疗方案敏感,预后良好 [47]。而在TCF3-ZNF384融合基因阳性患者中,一半以上患者有白细胞计数增高,大约一半患者对泼尼松龙反应不良,三分之一患者复发,预后差 [45]。目前已有研究报道EP300、TCF3、CREBBP功能及其功能丧失在ALL发生和复发中的作用 [45] [47] [48] [49],然而,BMP2K、SYNRG、ARID1B、EWSR1、TAF15在白血病发生中的作用尚不清楚,需要进一步研究ZNF384相关融合伙伴基因编码蛋白的分子基础,以阐明ZNF384及其融合伙伴基因异常在白血病发生中的确切作用机预后作用。

7. NUP214相关融合基因

NUP214 (CAN)基因位于9q34.1,是一种含有核孔蛋白的FG重复序列,其编码的蛋白质存在于核孔复合体的细胞质侧,是细胞周期和细胞核与质间物质运输的必要条件。迄今为止,已经发现5个NUP214伴侣基因,分别形成了SET-NUP214、NUP214-ABL1、DEK-NUP214、SQSTM1-NUP214、NUP214-XKR3融合基因。NUP214融合对白血病患者具有重要的诊断和治疗意义。在未来的研究中,还需要进一步鉴定与NUP214相关的融合。

(一) SET-NUP214融合基因

SET-NUP214融合基因在T-ALL中最常见,约占3.0%~10.3%,但在B-ALL、AML或急性未分化白血病中很少见,该融合基因阳性患者同时伴有HOXA簇基因高表达以及PHF6和NOTCH1基因突变 [50] [51]。由于SET-NUP214融合基因阳性儿童AL病例数量有限,其在儿童AL阳性率、临床特征有待进一步总结。研究报道,SET-NUP214融合基因阳性患者对皮质类固醇和化疗抵抗,治疗反应和预后较差,HSCT是目前最好的治疗策略 [50]。此外,SET-NUP214融合转录本可作为SET-NUP214阳性患者的MRD标记物 [51]。

(二) NUP214-ABL1融合基因

NUP214-ABL1融合基因在约6%的儿童和成人T-ALL中 [50],其染色体扩增是T-ALL患者特有的,有助于T-ALL诊断。该融合基因阳性患者通常存在T-ALL的高危因素,包括白细胞计数升高、纵隔肿块和髓质外受累,常伴有早期复发和预后不良,因此,早期利用MPseq及全外显子序列测定(Whole-exome sequencing, WES)检测该基因有助于指导治疗 [52] [53]。目前认为NUP214-ABL1融合导致了ABL1激酶的活性,TKI靶向治疗加标准化疗是一种有前途的治疗策略 [51] [52]。但有研究表明,NUP214-ABL1融合阳性患者ABL1表达异常与肿瘤发生无关,但与T-ALL的生长优势和耐药有关 [52]。

8. SIL-TAL1融合基因

SIL-TAL1融合基因仅见于儿童T细胞急性淋巴细胞白血病(T-cell acute lymphoblastic leukemia, T-ALL),因此可用于T-ALL辅助诊断。国内外报道T-ALL儿童SIL-TAL1融合基因阳性率不同,分别是33%和16% [54] [55],但是临床表现相似,初诊时白细胞计数高,肿瘤负荷大,治疗期间易出现肿瘤溶解综合征和弥散性血管内凝血,治疗效果均欠佳,其预后意义仍存在争议 [54] [55] [56]。研究表明,SIL-TAL1融合基因可作为化疗期间及allo-HSCT后MRD监测的可靠标志物,有助于评估临床疗效及指导治疗 [57]。

9. 结论

融合基因是儿童急性白血病的重要分子生物学标记,其形成与急性白血病的发生、发展、诊断、治疗、评估密切相关。据报道,不同的融合基因,其临床表现、诊断分型、预后转归均有差异。随着生物技术的飞速发展,融合基因的检测技术越来越多,包括染色体分析、FISH、实时定量PCR、RNA测序、环介导等温扩增(LAMP)、交叉启动扩增(CPA)、等温多重自匹配启动扩增(IMSA)、NGS、MPseq、WES、连锁阅读全基因组测序技术(WGS)等,充分掌握各技术的优缺点,选择适当的检测技术提高融合基因的检出率、敏感性、特异性,对于疾病诊断分型、监测肿瘤负荷情况、疗效判断有重要意义。当前急性白血病的治疗主要是化疗,国内外对融合基因靶向治疗均有研究 [18] [22] [28] - [33] [51] [52],而能够靶向治疗的融合基因相关类型白血病较少,因此,未来更多关于靶向治疗的研究为急性白血病的治疗提供新策略,显著改善患儿的预后,提高患儿的生存质量。

NOTES

*通讯作者。

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