与儿童急性髓细胞白血病相关的基因()-1

与儿童急性髓细胞白血病相关的基因突变

2008年，世界卫生组织对髓系肿瘤和急性白血病第三版分型方案进行了修订，基因突变在急性髓细胞白血病（AML）分型中的重要性被提到了一个新的高度，并新增了两个独特的AML临时亚型（Provisional entity），即“NPM1突变急性髓细胞白血病”和“CEBPα突变急性髓细胞白血病”【1】。随着基因测序技术的广泛应用，越来越多的基因突变被发现，基因突变在AML诊断、分型、治疗和预后中的重要作用也日见报道。本文总结近几年报道的与儿童急性髓细胞白血病（AML）相关的基因突变，以及对AML诊断、治疗和预后等方面的影响。与儿童急性髓细胞白血病相关的基因突变：

1、FLT3(fms-like tyrosine kinase)基因

FLT3(fms-like tyrosine kinase)基因，是Ⅲ型受体酪氨酸激酶（RTK）基因家族的一员，是急性髓细胞白血病（AML）相关基因中最易发生突变的一个【2】。

在AML中FLT3活化突变有三种：FLT3内部串联重复（internal tandem duplication，ITD）、酪氨酸受体区（tyrosine kinase domain，TKD）活化环点突变和近膜区（juxtamembrane domain，JMD）点突变。（1）FLT3-ITD：是FLT3基因最常见的突变形式，它在儿童AML中的发生率约10-15%【青少年44-47】。Zwan 等[青少年44]分析了234名儿童新发AML病人后发现FLT3-ITD阳性（FLT3-ITD（+））的病人年龄相对较大，并且该突变在正常核型和FAB分型为M1/M2型的AML中发生率更高。相反，在伴有染色体11q23异常或FAB分型为M5的儿童中FLT3-ITD突变很少发生。在儿童AML中，FLT3-ITD突变可导致病人的完全缓解(CR) 率、无病生存率(DFS)及总生存率（OS）均降低【7】，它是儿童AML的一个独立不良预后因素。（2）FLT3-TKD：发生率约7%-10%【12】，其对儿童AML预后的影响目前尚不十分清楚【13】。（3）FLT3-JMD：在AML中发生率约2%，FLT3-JMD 突变后的酪氨酸激酶同样可以被组成性活化和自磷酸化，但其转化活性较弱【14】。

野生型FLT3（wt- FLT3）高表达在AML病人中的发生率可达到80%【10】，但是其表达水平对AML病人预后的影响目前尚没有被清楚地确定。有报道，野生型FL T3的高表达有降低病人总生存率的倾向，但是差异没有统计学显著性【15】。也有人提出，随着野生型FLT3水平的升高，病人的临床预后相应变差【16】。

2、NPM1（nucleophosmin）基因

核磷蛋白（nucleophosmin, NPM、B23、NO38或NPM1）基因，定位于染色体5q35，编码核仁磷酸蛋白（NPM）。NPM在调节蛋白质合成、细胞生长和增殖，维持基因组的稳定性，以及细胞周期调节中起重要作用【28】。

在AML中，NPM1基因突变通常发生于12外显子（除外一些罕见的病例涉及第9和11外显子的拼接供体位点），其中最常见的‘A’型突变是一种在12外显子的956-959位点的TCTG四核苷酸重复【32】。2005年，Falini等报道了NPM1第12外显子的突变导致NPM蛋白在白血病原始细胞胞质中的异常定位，并将这类白血病细胞称之为NPMc+ 细胞【31】。

NPMc+ AML病人的临床特征：（1）NPM1突变的发生率随年龄增长而上升，并且常发生于正常核型AML （CN-AML）病人中。在成人AML中NPM1基因突变的发生率约25-53%，而在CN-AML中约占46-67%【28、31】。在儿童AML中NPM1突变的发生率相对较低（8.4%），同样集中于CN-AML亚组，约14-22%。3岁以下的儿童AML中没有检测到NPM1突变，而在3岁和更大年龄组中该突变的发生率稳定的保持在约10%【38、39】。（2）无论成人还是儿童，NPM1突变在女性AML患者中的发生率高于男性【28、38】。（3）NPM1突变的发生率还表现出种族差异，研究显示，亚洲人种中该突变的发生率较欧美国家来说显著较低【38-39、40-41】（4）NPM1突变在AML的各种FAB形态学亚型中都有发生。但M3型AML（急性早幼粒细胞白血病）中NPM1突变的发生及其罕见【28】。在儿童，NPM1突变仅在M1、M2 和M4亚型中被发现【39】。（5）NPM1突变还与其它的一些临床特征相关，包括：在初诊时伴有较高的白细胞（WBC）计数和较高的原始细胞百分比【28】；NPMc+ AML

病人髓外累及的发生率显著较高，最多见的是齿龈增生和淋巴腺病变【42】。

NPM1突变是一个新的预后相关分子标志，在儿童AML，尤其是CN-AML中NPM1突变提示良好预后，NPMc+ CN-AML应被归入中等危险度组【39】。Brown P等的研究显示，伴有NPM1突变的儿童AML与表达野生型NPM（wtNPM）者相比5年无事件生存率（EFS）要高（分别为50%和33%），但没有达到统计学显著性【38】。

3、CEBPA（CCAAT/enhancer binding protein α）基因

CCAA T/增强子结合蛋白-α（CCAA T/enhancer binding protein αCEBPA）基因定位于染色体19q13.1，其编码产物CEBPA蛋白是一个基础亮氨酸拉链(bZIP)转录因子。在造血组织中，CEBPA的表达对髓系祖细胞向粒系的终末分化和发育起着至关重要的作用【48】。

在AML中，CEBPA突变模式最主要的有两种，即N-末端揭短突变和bZip突变。这两种突变通常同时发生，形成CEBPA double-mut【53】，构成该类白血病发生的“两次打击”【55】。CEBPA突变在儿童AML中的发生率约6%【58】，Ho PA等【55】分析了847例儿童AML病例，在4.5%的病例中检测到CEBPA突变（82%含有两种类型的突变），并且发现CEBPA突变更多发于较大年龄组、FAB分型为M1或M2亚型，以及染色体核型正常的病人。CEBPA突变与较低的复发率和较好的生存率相关，并且是儿童AML的一个良好的独立预后因素。然而，Wouters 等发现只有两种类型的CEBPA突变一起发生所形成的特殊基因表达谱才与良好预后相关【青少年55】。最近有研究显示：在新发AML中，CEBPA基因的高甲基化是一个良好预后标志【59】。

4、c-Kit基因

原癌基因c-Kit，其编码产物为干细胞因子受体CD117，属于受体酪氨酸激酶（RTK）家族。其配体是干细胞因子（SCF），这一受体配体结合在造血、黑色素生成、配子形成和细胞的增殖、分化、存活和迁移中起着重要作用【60】。

c-Kit基因突变有两种形式：一种是酪氨酸激酶的组成性活化（constitutively activated）突变，通过引起信号转导的异常导致细胞过度增殖和存活。另一种是能够引起转录因子功能缺失（loss of function）的突变，这对于造血活动中细胞分化很重要【61】。据报道在成人和儿童AML中c-Kit突变的总发生率约17%【62-64】，且通常发生在核心结合因子（CBF）AML病人中（约占52%）【65】。在儿童AML中，c-Kit突变的发生率约18%：4%涉及第8外显子，7%涉及17外显子，另有7%涉及JMD/KD（近膜区结构域/激酶结构域)，在CBF-AML病人中还鉴定出一种涉及到第11和12外显子的ITD复合物【64】。

c-Kit突变对儿童AML临床后果的影响尚不十分明确。Goemans 等【青少年59】通过对150名AML儿童进行研究，未发现c-Kit突变与预后有显著相关性。Lapillonne 等【69】则报道了三例伴有inv(16)和c-Kit突变的儿童AML预后极好。然而，Shimada等【70】的研究则发现c-Kit突变与儿童CBF-AML（尤其是t(8;21)(q22;q22)）的不良预后紧密相关。

5、WT1（Wilms' tumor 1）基因

WT1（Wilms' tumor 1）基因，目前被认为可以调控造血细胞的生存、增殖和分化【75】。该基因含10个外显子，可发生多种转录水平的改变，在AML中表达的主要是含有第5外显子改变的WT1亚型【76】。

WT1基因突变在成人CN-AML中的检出率约10%，与不良预后相关【青少年62、65】。该突变在儿童AML 中的发生率更高，约12%，且主要集中于CN-AML亚组（约22%）。WT1突变的发生率与年龄显著相关，小于3岁组中该突变的发生率仅2%，而3至10岁组则达18%【青少年66】。Hollink 等发现伴有WT1突变的AML 儿童发生早期耐药和复发的几率增高，目前WT1突变已被认为是儿童AML中新发现的独立不良预后标志【青少年2、66】。

另外，约73-93%的新发AML病人存在WT1基因的高表达【77】，在儿童AML中，若诱导化疗结束后仍有

WT1基因的高表达预示着高复发和死亡风险【78】。因而，以WT1表达水平作为MRD的检测指标对儿童AML 复发和死亡风险的预测有重要意义，并且对于复发的早期监测很有帮助【79、80】。

6、Ras基因

Ras基因亚家族有21个成员，比如：H-Ras, K-Ras (A和B), N-Ras, 以及其他的多个成员【94】。Ras原癌基因的活化突变在许多类型的人类肿瘤中经常发生，包括MDS（骨髓增生异常综合症）和AML【95】，其中N-Ras 基因缺陷更是青少年粒单核细胞性白血病（juvenile myelomonocytic leukemia JMML)的重要病因【98】。在儿童AML中Ras基因突变的发生率约18%，而且，病人即便没有Ras基因突变，Ras依赖性的信号转导通路也会经常受到其他相关基因（如：FLT3,c- Kit, 和PDGFR）突变的影响【99】。Ras突变对AML预后的提示意义还不是非常明确。Goemans 等【102】发现Ras突变常发生于CBF-AML或CN-AML中，其对临床后果的影响无显著性。相反，Lapillonne 等【69】则发现N-Ras突变与预后不良的染色体核型（主要是t(6;9)）相关，并且对于AML 儿童的无事件生存率（EFS）和总生存率（OS）是独立的不良预后因素。

7、MLL (Mixed Lineage Leukemia，混合谱系白血病)基因

混合谱系白血病（Mixed Lineage Leukemia，MLL）基因，位于染色体11q23，其编码的MLL蛋白在造血细胞中广泛表达，在胎儿肝脏和成人骨髓造血干细胞自我更新中起着至关重要的作用【104】。MLL蛋白具有甲基转移酶活性，调节造血干细胞发展过程中HOX基因的表达【105】。

MLL-PTD（partial tandem duplication，部分串连重复）突变是CN-AML中第一个被描述的分子异常，该突变导致野生型MLL蛋白的所有功能区发生局部重复。MLL-PTD在CN-AML中的发生率约5-10%，对于成人AML 它并不总是带来不良预后【青少年67】。而在儿童AML中，MLL-PTD突变的发生率约13%，并且与不良后果相关【108】。

8、DNMT3A（DNA methyltransferase-3A ，DNA甲基转移酶-3A）基因

DNA甲基转移酶-3A（DNA methyltransferase-3A，DNMT3A）基因，含有24个外显子，编码产物DNMT3A 蛋白是甲基转移酶家族中的一员，可催化甲基化基团添加到序列中含有CpG双核苷酸的DNA上【131】。Ley 等【132】利用巨大并行的DNA测序技术在一例正常核型AML病人的白血病细胞基因组中鉴定出了DNMT3A的体细胞突变。他们继而分析了一个大样本成人AML群体（281名病人）的DNMT3A基因外显子序列，发现其中22.1%（62人）的病人含有DNMT3A体细胞突变。并且依据初诊时的细胞遗传谱进行分类，伴有DNMT3A 突变的病人绝大多数属于中等危险度组。还鉴定出了18种不同的错义突变（其中最常见的一种可影响氨基酸R882）、6中框移突变、6种无义突变和3种剪接位点突变，还有一个包含DNMT3A的1.5Mbp的缺失。

目前，在AML中发现的DNMT3A突变有两种类型：一种突变可导致蛋白质功能的丧失，即功能失活性突变；另一种突变是由CpG双核苷酸上碱基C（胞嘧啶）向T（胸腺嘧啶）转换所造成的，可影响氨基酸位点R882上精氨酸密码子【133】。这两种突变对AML病人的临床和生物学特征的影响是相近的，不同的是伴有R882突变的病人在初诊时通常外周血白细胞计数较高【132】。

DNMT3A突变在AML病人中反复发生，在不考虑年龄和FLT3或NPM1基因突变，以及突变类型或基因定位的情况下，它与不良的无事件生存率（EFS）和总生存率（OS）相关。它还是白血病复发强有力的独立预测因素【131】。最近，上海血液学研究所通过全外显子组捕获和第二代测序技术，成功获得了14例AML-M5（急性单核细胞白血病）患者白血病细胞的蛋白质编码区的序列信息。经过有效的生物信息学过滤分析以及全外显子扩大规模测序验证，发现DNMT3A基因在M5型白血病中突变率高达20.5%，其中累及第882位精氨酸密码子的突变频率达18.8%。存在这一基因突变的患者治疗效果很差，完全缓解率低，患者的平均生存期通常只有7个月，

而无此突变的患者平均生存期则可达到约19.5个月。这提示该基因的突变与患者的不良预后密切相关，在今后的治疗中对携带此基因突变的患者可能需要采取更为积极有效的治疗方案【陈赛娟】。另外，对儿童AML样本进行DNMT3A突变的分析也很重要，Ley等【132】发现伴有DNMT3A突变的病人接受干细胞移植（HSCT）可以取得较好的预后，因而DNMT3A突变的存在可能有助于告知在达到第一次完全缓解（CR）后进行异基因HSCT的合适时机。

各种常见基因突变之间的相互关系：

在AML，尤其是CN-AML中，关系最密切的两个基因是FLT3和NPM1，有研究显示：与伴有FLT3和NPM1双突变或双不突变的AML相比，NPMc（+）/FLT3-ITD（-）病人的无事件生存率（EFS）和总生存率（OS）最高【38】，提示这类病人预后相对良好。然而，NPM（-）/FLT3-ITD（+）病人的临床后果显著较差【129】。另外，FLT3-ITD突变是与WT1突变关系最为密切的一种突变，这两种突变同时存在时会导致极度不良的预后【91】。然而，WT1和NPM1突变似乎是两种相互排斥的突变，几乎不会同时发生【66】。在AML细胞基因组中，DNMT3A 基因突变与其它常见的AML相关基因之间也存在相关性。在伴有DNMT3A突变的样本中FLT3、NPM1基因突变显著高发，而在涉及染色体11q23（MLL基因的定位区）结构的改变的AML病例中很难检测到DNMT3A突变【132】。

各种基因突变对AML治疗的影响：

深入认识与AML相关的各种基因突变不仅有助于临床诊断和预后评估，还能为更加合理、有效的治疗策略的制定和选择提供新路径。酪氨酸激酶的活化和下游信号转导在AML中十分重要。FLT3和c-Kit突变可直接导致酪氨酸激酶的组成性活化和下游信号传递，因此酪氨酸激酶抑制剂（TKIs）用于AML的治疗可成为一种潜在的治疗策略。FLT3是AML中最易发生突变的基因，被认为是AML极有前景的治疗靶点。目前已有三种类型的药物作为FLT3抑制剂用于AML的分子靶向治疗：FLT3单克隆抗体、热休克蛋白抑制剂和酪氨酸激酶抑制剂（tyrosine kinase inhibitors (TKIs)）。作为FLT3抑制剂的TKIs通常对FLT3有较高选择性，目前已有多种被研制出来，并进入临床试验【18-20】。TKIs用于伴有c-Kit突变的AML病人可产生潜在的治疗效用，如：Dasatinib (BMS-354825)、Sorafenib、sunitinib (SU11248)在临床前研究中显示出良好的疗效，甚至对于难治性AML有效，但他们的临床疗效有待进一步明确【72、73】。另外，WT1基因有望成为免疫治疗的潜在有效靶点。有研究在AML病人中开展试验性WT1免疫治疗，结果使病人获得完全缓解（CR），并且都证明可诱发有效的肿瘤免疫和WT1特异性细胞毒性T淋巴细胞（CTL）的发育【81、82】。近期的一项在19名AML病人中开展的WT1疫苗Ⅱ期临床试验中有14人对WT1疫苗有客观反应，显示出WT1免疫治疗的潜在效用【83】。而法呢酰基转移酶抑制剂（FTIs）则被证明对具有RAS基因突变的病人有效【】。还有，DNMT3A、MLL基因突变所致的DNA和组蛋白的甲基化等表观遗传学改变参与AML的发生机制，用去甲基化药物（如：氮杂胞苷和地西他滨）进行表观遗传学调节已经被用于AML的临床治疗【陈赛娟】。

总结：

急性髓细胞白血病（AML）是一种在临床表现和分子生物学方面都存在明显异质性的人类恶性肿瘤，大量分子水平的异常参与其发生、发展，决定其诊断、分型和治疗，影响其预后。FLT3、c-Kit、WT1、NPM1、CEBPA、MLL和DNMT3A等基因突变对儿童AML病人预后的评估很重要（表1），以上列出的即是目前研究已较明确，对儿童AML病人的临床管理影响较大的分子改变。随着分子生物学技术的进展及其在临床医学中的应用，各种新的研究成果日益涌现，对AML进行分子靶向治疗的新策略有望在不久的将来逐渐与传统的化学治疗相结合形成更加具有特异性和个体化的合理治疗方法，从而改善AML儿童的治疗反应和生存率，使其获得更高质量的预后。

表（1）本文中涉及到的AML相关基因异常在儿童AML中的发生率及其对预后的影响

分子异常在儿童AML中的发生率对儿童预后的影响参考文献

LT3-ITD突变10％~15％–Thiede et al.【4】; Zwaan et al.【7】

PM1突变约8.4% + Brown et al.【38】; Hollink et al.【39】EBPA突变约6% + Liang et al.【58】; Ho PA et al.【55】

Kit突变约18% –Corbacioglu et al.【64】; Shimada et al.【67】T1突变约12% –Hollink et al.【91】; Owen et al.【93】

as突变约18% +/- Emanuel et al.【98】; Goemans et al.【102】

Lapillonne et al. 【69】

LL-PTD 约13% –Shimada et al.【108】

NMT3A突变（—）–Shannon et al. 【表观遗传学】备注：+，良好影响；-，不良影响；+/- 目前尚不清楚或研究结果又分歧；（—）暂无确切报道。

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