CEBPA bZIP 框内突变在急性髓系白血病中的研究进展

来源期刊：广州医药 | 139-150 发布时间：2025-02-20 收稿时间：2025/3/4 16:47:51 阅读量：77

作者：: 陈克敏,

黄志斌,

王顺清,

张文清,

关键词：: 急性髓系白血病 CCAAT增强子结合蛋白A bZIP框内突变; acute myeloid leukemia CCAAT enhancer-binding protein A bZIP in-frame mutations

DOI：: 10.20223/ j.cnki.1000-8535.2025.02.001

收稿时间：: 2024-08-20
修订日期：
接收日期：
引用总数：: 0

CCAAT增强子结合蛋白A（CEBPA）是调节血液发育过程中髓系分化和造血干祖细胞活性的关键转录因子之一。CEBPA基因突变常见于急性髓系白血病（AML）中，最近研究表明CEBPA bZIP框内单位点和经典双等位基因突变AML患者均具有类似的临床特征，已被单独划分为AML亚群。CEBPA bZIP框内突变而非传统的双等位CEBPA基因突变成为AML良好预后的分子指标，表明其在AML疾病进展和治疗预后中的重要性和特殊性。本文将从CEBPA蛋白在血液系统中的功能、CEBPA bZIP框内突变AML的临床特征与分子作用机制、以及伴CEBPA突变AML的治疗现状等方面进行综述，为进一步研究CEBPA bZIP框内突变在AML中的致病性和精准治疗新药物开发提供参考。

张文清 博士，华南理工大学医学院二级教授、博士生导师、医学院副院长，教育部发育与疾病医药基础研究创新中心PI，华南理工大学发育生物学与再生医学团队负责人、细胞生物学教研室主任，中国动物学会斑马鱼分会常务理事、深圳湾实验室同舟学者。担任《广州医药》杂志副主编，主要从事造血发育、疾病模型与药物筛选研究，获各类国家自然科学基金13项，科技部973、863及重点研发课题4项，广东省自然科学基金团队项目1项。以通讯作者在Blood、Nature Communications、Leukemia、eLife、Development、JBC等SCI期刊发表论文35篇，合作作者发表SCI论文38篇，相关斑马鱼白血病模型专利授权4件。

王顺清 医学博士，主任医师，博士生导师。广州市第一人民医院（华南理工大学附属二院）内科兼血液内科主任，中国医师协会血液科医师分会委员，中华医学会血液学分会红细胞疾病学组委员，广东省医学会血液病学分会副主任委员，广州市医学会血液学分会主任委员等。从事血液病学临床、教学和科研工作30余年，主要研究方向是再生障碍性贫血诊治、造血干细胞移植以及细胞治疗和基因治疗。主持和参与国家重点研发计划、国家自然科学基金以及省市各级科研项目20余项，发表论文100余篇，其中SCI收录70余篇，获省市成果6项，专利7项。

急性髓系白血病（acute myeloid leukemia，AML）是一种具有高异质性的血液系统恶性疾病，以髓系细胞分化障碍和前体细胞克隆性增生为主要特征^［1］。AML在人群中的年均发病率约为十万分之五，但平均5年生存率仅约30%^［2-3］，其复杂且尚不明确的致病机制给临床诊断及治疗带来了巨大挑战。驱动白血病细胞形成及恶性克隆转化的特定基因突变对临床AML患者的分类诊断及个性化治疗有重要指导意义^［4-5］。

CCAAT增强子结合蛋白A（CCAAT enhancer-binding protein A，CEBPA）基因突变常被发现于5%~14%正常核型初发AML患者中，其突变类型包括单位点突变和双等位基因突变^［6］。相较于西方和部分东亚国家如日本和韩国，中国AML病人中CEBPA基因突变频率更高，可达到20%^［7］。CEBPA基因突变主要包括发生于氨基端（N端）的移码突变（frame-shift mutation）（导致全长P42蛋白翻译提前终止并产生截短型P30蛋白）和羧基端（C端）碱性亮氨酸拉链（basic region and leucine zipper，bZIP）区域的框内突变（in-frame mutation），两种突变组合即为经典的CEBPA双等位基因突变（biallelic mutation）^［6，8］。早期临床研究发现，携带经典CEBPA双等位基因突变的AML患者具有类似的临床特征和分子基因表达谱，且预后良好^［9-10］。2016年，WHO首次将伴CEBPA双等位基因突变的AML单独归类^［11］。近年研究发现，携带单位点CEBPA bZIP框内突变的患者与双位点突变患者的临床和分子特征一致^［12］。同时，2022年WHO和国际共识分类（ICC）标准将AML伴CEBPA双等位基因突变亚群修订为AML伴CEBPA突变（bZIP框内突变）^［13］。这一转变强调了CEBPA bZIP框内突变而非N端移码突变在AML 发生发展及治疗预后中的关键的致病作用，但目前缺乏实验数据证实。此外，针对伴CEBPA突变AML这一特殊亚群，尚缺乏精准治疗药物，仍采用广谱抗增殖诱导化疗，尽管疗效较其他CEBPA未突变的AML患者更好，但仍面临复发及长期生存率不佳的问题。本文总结了CEBPA bZIP蛋白的结构和功能、CEBPA突变AML的基本特征、致病机制及治疗现状，以期加深对CEBPA bZIP框内突变AML的理解。

1 CEBPA 基因、蛋白结构及其功能概述

CEBPA作为CEBP转录因子家族的核心成员，归类于bZIP蛋白超家族，具有高度保守的DNA结合碱性区域（basic region，BR）和二聚化所需的亮氨酸拉链（leucine zipper，LZ）结构（图1A）^［14］。CEBPA基因为单外显子基因，其mRNA序列包含特殊的上游开放阅读框（upstream open reading frame，uORF）结构，且存在多个可起始翻译的AUG密码子，能够翻译多种不同长度的蛋白亚型^［15］。其中，主要的功能亚型包括生理性高表达的全长蛋白P42（从ORF第一个AUG起始翻译）和病理性高表达的截短型P30（从ORF第三个AUG起始翻译表达）^［15］。P42蛋白通过C端的bZIP结构域形成同源或异源二聚体，直接结合靶基因的上游启动子或增强子序列，通过N端的两个转录激活结构域（transactivation domain，TAD）发挥转录调控作用^［16-17］。P30蛋白缺少第一个TAD结构域，其转录调控活性较P42减弱，但可结合共同的靶DNA序列，P30可通过竞争性与CEBPA P42或其他bZIP蛋白二聚化，发挥显性抑制效应（dominant-negative effect），并具备P30特异的获得性功能（gain-of-function），此两种特性被视为CEBPA N端移码突变导致AML的潜在促癌机制^［8，18］。值得注意的是，P30与P42的转录调控作用均依赖于C端bZIP结构域的完整性与正常功能。bZIP结构域由DNA结合碱性区、亮氨酸拉链重复序列及铰链区构成，同时包含多个核定位信号^［16］。其中，亮氨酸拉链结构域是经典的螺旋卷曲结构，相邻螺旋表面的氨基酸残基通过疏水相互作用形成稳定的二聚体结构^［19］。CEBP蛋白只有在二聚化后，才可通过碱性区域结合DNA并对靶基因进行转录调控，行使其蛋白功能^{［16，19］}。

图 1 人类 CEBPA 蛋白结构和血液系统功能示意图

注：（A）人类全长型CEBPA P42蛋白由358个氨基酸构成，包含两个转录激活结构域（TAD1、TAD2）和碱性亮氨酸拉链结构域（bZIP）。其中，bZIP由碱性区域（BR）和亮氨酸拉链结构域（LZ）共同组成，分别行使结合DNA和二聚化功能。（B）造血发育过程中，CEBPA蛋白可直接结合或与其他蛋白因子共同作用间接结合靶基因启动子区域，激活髓系分化及抑制细胞增殖相关基因表达，参与造血干祖细胞和髓系细胞发育过程。

CEBPA基因和蛋白结构及功能在多种生物（如人、小鼠、斑马鱼）中均高度保守。在血液系统中，CEBPA主要参与髓系细胞的分化过程。已有研究发现，不同类型的CEBPA突变小鼠和斑马鱼均表现出中性粒细胞和单核-巨噬细胞等成熟髓系细胞的减少或缺失^{［20–23］}。在髓系发育早期，CEBPA通过直接作用或与RUNX1、PU.1等髓系发育调节因子协同作用，激活髓系相关基因（如Gfi1、Egr1、Klf5、Csf1r、Cebpe、Mpo、Csf3r），并抑制非髓系相关基因（如Epor、Lck）的表达，从而促进共同髓系前体细胞（common myeloid progenitor，CMP）向粒-巨噬前体细胞（granulocyte-macrophage progenitor，GMP）分化，并诱导粒细胞的终末分化^［24-25］。此外，CEBPA还参与细胞周期的调控，与E2F、P21、CDK2/4等细胞周期蛋白共同作用，阻止细胞从G1期进入S期，抑制前体细胞增殖并促进分化（图1B）^［26］。

然而，关于CEBPA在维持造血干/祖细胞（hematopoietic stem/progenitor cell，HSPC）活性方面的具体作用机制，目前仍存在争议。一方面，CEBPA可能参与维持HSPC的静息状态，另一方面，也有证据表明它可能促进HSPC的自我更新^［24-25］。这种争议在不同条件下的Cebpa敲除小鼠模型中得到了体现，其HSPC的数量、增殖凋亡状态及造血重建能力均表现出截然不同的结果。值得注意的是，在cebpa^rj31突变斑马鱼模型中，尽管Cebpa的功能受到影响，HSPC的数量及非髓系造血（如淋巴细胞、红细胞）发育并未受到显著影响^［27］。然而，本团队最新研究发现，斑马鱼cebpa全基因敲除会阻碍HSPC的产生及自我更新，并导致定向造血缺陷^［28］。综上所述，CEBPA在血液系统中的作用阶段广泛、细胞类型多样、作用机制复杂，其基因突变或功能障碍易导致AML的发生与发展。

2 AML 相关 CEBPA bZIP 框内突变的基本特征及其临床意义

AML患者中，CEBPA基因的突变以体细胞突变为主，其突变位点和方式展现出高度的复杂和多样性。其中，CEBPA双等位基因突变占比约60%，以同时伴随N端（第1-120位氨基酸）的移码突变和C端bZIP（第278-345位氨基酸）框内突变的经典双等位基因突变为主，双等位单一N端或C端突变非常少见^［29-30］。相较之下，CEBPA单位点突变可发生于任意区域，bZIP框内突变约占30%，且此类突变患者与经典双位点突变患者展现出相似的临床分子特征^［30-31］。因此，bZIP框内突变被独立归类，其总体占比高达70%。尽管CEBPA其他区域或bZIP区域内的移码突变和无义突变也存在，但相对罕见，且与临床预后及其他临床特征无直接关联（图2）^［32］。

图 2 AML 患者中 CEBPA 基因突变类型

注：临床AML患者中，CEBPA基因突变多为发生于N端移码突变产生截短型P30蛋白及C端bZIP结构域框内突变的经典CEBPA双等位基因
突变，且单位点和双等位CEBPA bZIP框内突变患者具有类似的临床特征。

2001年，T Pabst等人^［33］首次报道了AML患者中存在CEBPA基因的杂合突变。2009年，Delwel R团队^［9］首次发现，携带CEBPA经典双等位基因突变的AML患者具有一致的基因表达特征，且表现出较高的生存率（总体生存率＞60%），而CEBPA单位点突变AML患者的整体预后则不佳，与未突变AML患者相比无明显差异（总体生存率均＜30%）。基于这些发现，WHO于2016年将伴CEBPA双等位基因突变的AML进行独立分类^［11］。

直至2021年，来自日本的Wakita团队^［12］和来自美国的Tarlock团队^［34］分别通过1 028例成人和2 958例儿童白血病患者的临床病例分析，进一步揭示了单位点CEBPA bZIP框内突变与双等位基因突变患者临床中的临床预后特征没有显著差别，均表现出较高的无事件生存率、总体生存率和较长生存期，并具有相似的基因表达谱。同时，Tabue等人^［31］通过对4 708例AML患者的队列研究进一步巩固了该结论，指出CEBPA bZIP框内突变（无论是单位点还是双等位突变）的AML患者不仅预后良好，还具有发病年龄较早、白细胞计数高以及共突变基因较少且特定（如GATA2、TET2、WT1等）等特征，与未突变和非bZIP框内突变患者存在显著性差异。这一系列研究结果均强烈暗示bZIP框内突变是CEBPA突变AML独特临床特征的关键决定因素。因此在欧洲白血病网（European Leukemia Net，ELN）最新发布的AML风险预后分层分类标准中，已将CEBPA双等位基因突变更新为CEBPA bZIP框内突变，并将其纳入良好预后指标^［13］。近年来，国内外多项临床病例数据分析持续证实了仅CEBPA bZIP框内突变AML患者预后良好的结论^［35-36］。最新研究中，Georgi等人^［37］进一步揭示了bZIP框内突变的具体特征，指出其主要为框内插入或缺失突变，而单个氨基酸改变的错义突变相对较少。此外，他们发现bZIP错义突变相对集中于DNA结合碱性区域和亮氨酸拉链结构域，而插入/缺失突变则在铰链区，特别是K312和K313位点表现出更高的突变频率，这进一步补充了CEBPA bZIP框内突变的分布特征。

3 CEBPA P30 和 bZIP 框内突变蛋白导致 AML发生的作用机制研究进展

近二十年来，研究者们借助一系列动物和细胞模型，深入探究了CEBPA双等位基因突变，特别是N端移码突变所产生的P30蛋白在AML疾病进展中的促癌作用。全基因敲除Cebpa的小鼠胚胎致死，而条件性敲除Cebpa的小鼠模型则揭示了CEBPA缺失会导致GMP生成障碍^{［20，22］}。鉴于GMP的形成是AML发病的关键环节，CEBPA在维持部分髓系分化功能方面的作用对于AML的发生至关重要^［38］。利用Cre-loxp系统，Porse团队^［21］首次成功构建了仅表达截短型CEBPA P30的小鼠模型，该模型模拟了AML患者中的N端移码突变，研究发现P30蛋白虽然能促进GMP生成，但不足以维持粒细胞和巨噬细胞的终末分化。随着转录组和蛋白组测序技术的发展，除了发现P30蛋白的转录激活作用减弱并竞争性抑制全长P42或其他bZIP蛋白功能外，还揭示了P30具有独特的转录调控作用和特定的蛋白分子相互作用网络^［8］。利用PRISMA和Bio-ID技术，Ramberger等^［39］鉴定出了多个P30特异性结合的蛋白分子，包括GATA1、BCL11A、TFAP4、BLM等。此外，研究者们还相继发现SUMO修饰途径中的E2酶UBC9^［40］、AMP水解限速酶CD73^［41］、RNA结合蛋白MSI2^［42］是CEBPA P30直接作用的靶因子，P30能够激活这些促癌因子的表达，从而加速AML的进展。因此，CEBPA N端移码突变一直被认为是CEBPA突变导致AML的关键致病因素。然而，最新研究表明，无论P30是否表达，CEBPA bZIP框内突变AML患者均展现出类似的临床分子特征^{［12，31］}，这提示P30可能仅作为协同促白血病转化的因素，而CEBPA bZIP框内突变蛋白在AML致病过程中发挥着更为关键的作用。

2001年，Porse等人^［43］率先揭示了CEBPA BR区域非DNA结合氨基酸位点的错义突变（如BRM2、BRM5）虽然保留了转录激活作用，但破坏了CEBPA与细胞周期调节蛋白E2F的结合，导致脂肪细胞和粒细胞生成障碍。随后，他们利用BRM2基因敲入小鼠模型进一步发现，丧失CEBPA介导的E2F抑制作用可直接调控细胞周期进程，促进髓系前体细胞增殖并抑制髓系分化，从而促进AML细胞的恶性生长^［44］。通过突变位点氨基酸序列分析及体外细胞生物化学实验验证，部分发生在AML患者中的CEBPA铰链区或LZ区域插入/缺失突变（如K312dup、A305P）被证实会破坏bZIP蛋白的α-螺旋稳定性，干扰其与下游靶基因G-CSFR启动子DNA序列的结合^［45］。类似地，Togami等人^［46］在32Dcl3细胞中过表达bZIP框内突变蛋白的研究发现，S299_K304dup、K313dup、N321D等突变蛋白均具有不同程度的抑制髓系分化作用，其中，N321D突变蛋白显著下调了Csf1r基因的表达，表现出对白血病细胞疾病进程的阻碍作用，提示可能存在其他调节因子在加速AML进展中发挥作用。需要注意的是，以上研究多局限于体外细胞实验，且多通过过表达突变蛋白来探究其生物学功能的改变，因此难以真实模拟内源性CEBPA bZIP框内突变导致AML发生的复杂疾病进程。

2009年，Nerlov团队^［47］首次成功构建Cebpa双位点突变AML小鼠模型，通过CEBPA^K313KK敲入小鼠精确模拟AML患者中的高频bZIP框内突变（K313dup）并发现该单位点纯合突变小鼠中髓系发育被阻滞在前体细胞阶段，且长期造血干细胞增殖和移植后造血重建能力显著高于野生型造血干细胞。这表明C端bZIP框内突变通过促进造血干细胞增殖是加速白血病细胞形成的重要细胞学机制。进一步研究中，Gentle等人^［48］发现CEBPA^K313KK突变促进了CEBPA蛋白多个亚型的表达，并可能与其他转录调节因子如SPI1或PU.1协同作用，增强对CEBPA靶基因的转录激活，从而促进髓系前体细胞增殖并向白血病细胞转化。这一发现更新了人们对CEBPA bZIP框内突变削弱其生物学功能的认识，强调了CEBPA蛋白结合DNA能力并非是决定其转录调控活性强弱的唯一因素。

Bararia等人^［49］发现，赖氨酸乙酰转移酶GCN5介导的CEBPA bZIP区域K298和K302位点的乙酰化修饰显著降低了其转录调控活性，进而抑制了CEBPA的促髓系分化作用。此外，在AML患者细胞中观察到乙酰化CEBPA蛋白水平的显著升高，这表明CEBPA蛋白的翻译后修饰变化可能参与AML发病机制。最近，Ye团队^［50］首次发现CEBPA蛋白可通过其bZIP结构域特异性地结合甲基转移酶DNMT3A并抑制其活性。并且，多种与AML相关的bZIP框内突变会破坏这种结合，导致基因组DNA的高甲基化，进而降低PRC2靶基因的表达，最终促进白血病进展。此外，Wang等人^［51］发现，bZIP结构域还参与CEBPA蛋白的液-液相分离过程，而抑制LZ结构域的同源二聚化可干扰蛋白凝聚体的形成，从而降低其转录调控活性。然而，AML相关的bZIP框内突变是否通过该途径影响蛋白功能仍需进一步实验证实。

以上研究结果表明，CEBPA bZIP不同位点的突变在减弱其促髓系分化及/或抑制前体细胞增殖能力方面的作用机制不尽相同。这些突变可能导致DNA结合能力减弱，从而影响CEBPA蛋白的转录调控功能，或通过干扰与其他蛋白因子的相互作用，直接或间接地抑制髓系分化并促进白血病细胞增殖（图3）。这进一步凸显了CEBPA突变AML的高度异质性，可能对该类亚群患者的临床治疗构成挑战。

图 3 CEBPA bZIP 框内突变蛋白作用机制

注：CEBPA bZIP框内突变蛋白可通过降低CEBPA蛋白DNA结合能力、破坏蛋白相互作用、影响蛋白乙酰化修饰、蛋白表达水平等多种
途径直接或间接阻碍髓系细胞分化并促进前体细胞增殖，导致AML疾病的发生发展。

4 CEBPA 突变 AML 的临床治疗及潜在治疗靶点

目前，AML的临床治疗首选方案仍然是阿糖胞苷联合柔红霉素或4-去甲柔红霉素的“3+7”诱导化疗^［52-53］。该化疗药物通过直接作用于细胞周期，抑制细胞增殖并细胞凋亡，从而发挥高效的抗肿瘤作用^［52］。对于CEBPA bZIP框内突变的AML患者，经过强化诱导治疗后，其完全缓解率可超过80%^［54］。然而，尽管异基因造血干细胞移植在减少化疗后复发方面显示出优势，但在第一次完全缓解期（CR1）后，与巩固化疗相比，并未显著提升长期生存率^［55］。CEBPA突变AML患者的合并基因突变类型及治疗期间的微小残留病灶（minimal residual disease，MRD）水平对标准化疗效果具有重要影响。研究表明，合并CSF3R基因突变的CEBPA双突变AML患者相较于CSF3R未突变患者，复发风险更高，且5年生存率较低^［56］。此外，合并WT1或DNMT3A基因突变与CEBPA bZIP框内突变AML患者的不良预后相关，这些不良预后患者的无事件生存期较短，且其AML细胞中干扰素信号通路和线粒体代谢相关基因表达较高，提示AML细胞的免疫代谢状态可能影响其药物反应性^［57］。Wang等人^［58-59］发现，治疗后MRD阳性的CEBPA突变AML患者3年期总体生存率（64.7%）显著低于MRD阴性患者（96.2%），并将2疗程巩固化疗后MRD仍呈阳性的情况视为高风险预后因素。根据最新ELN指南，针对MRD持续阳性的高风险CEBPA bZIP框内突变AML患者，建议在第一次完全缓解期（CR1）后选择异基因造血干细胞移植以提高总体生存率；若患者无法耐受高强度化疗（如年龄＞60岁），则可考虑采用维奈克拉联合去甲基化药物的替代方案^［60-61］。然而，Zhang等人^［36］的队列研究发现，该种组合药物治疗效果在1年无复发生存率和总体生存率方面较标准化“3+7”化疗方案低。综上所述，CEBPA突变AML的临床治疗方案及其疗效仍有待进一步优化和提升。

随着对白血病分子病理学的深入理解，针对CEBPA突变的AML靶向治疗策略正逐步显现其潜力。尽管尚未实现临床应用，但基于动物和细胞模型的研究已取得了显著进展。Tenen团队^［62］发现，CEBPA可直接抑制癌基因Sox4的表达，并表明通过小鼠和细胞模型靶向敲低SOX4，可显著降低CEBPA突变白血病细胞的异常增殖活性并促进其髓系分化潜能。Jakobsen等人^［41］鉴定出截短型P30特异激活的促癌因子CD73在CEBPA双等位基因突变AML细胞中高表达。通过靶向抑制CD73/A2AR信号轴，可发挥较好的抗肿瘤效应。类似地，P30特异性激活的UBC9和MSI2也都被视为潜在的药物治疗靶点^{［40，42］}。Schmidt等人^［63］发现MLL1抑制剂可有效缓解P30-MLL1复合体相互作用介导的促白血病进展。此外，CEBPA双突变AML患者对JAK抑制剂表现出高敏感性^［64］以及JAK和LSD1抑制剂联合应用在合并CSF3R突变的AML细胞中效果更佳^［65］，这表明多靶点联合治疗策略在这类疾病中的巨大潜力。Ye团队^［50］发现DNMT抑制剂——地西他滨可有效杀伤携带CEBPA^N321D突变的AML细胞，并抑制其成瘤能力。综上所述，当前的研究主要集中在通过干扰P30特异促癌因子的表达或功能来实现抗肿瘤作用，但针对bZIP框内突变蛋白致病的特异性药物作用研究仍需进一步深入（图4）。

图 4 伴 CEBPA 突变 AML 治疗现状

注：CEBPA突变（bZIP框内突变）AML患者依然面临化疗后复发的治疗困境。针对该特殊亚型，未来的靶向/精准药物治疗研究
需由促癌蛋白P30的靶分子转向bZIP框内突变蛋白。

AML细胞的核心特征在于髓系前体细胞的克隆性增殖和分化障碍^［1］。鉴于这一病理基础，治疗策略已逐渐拓展至不仅限于抑制细胞增殖，还包括诱导白血病细胞向成熟髓系细胞分化，这在AML （全反式维甲酸）联合砷剂在治疗特定的治疗中展现出新的希望。特别地， AML ATRA 亚型——急性早幼粒细胞白血病（acute promyelocytic leukemia，APL）上取得了里程碑式的成功，其长期缓解率可超过90%，显著延长了患者生存期，并实现了高治愈率^［66-67］。然而，由于ATRA的特异性作用机制依赖于PML-RARA癌蛋白，其在非APL的AML患者中的疗效并不理想^［68］。APL在FAB分类系统中被归为AML-M3型，其特征是细胞质富含颗粒的早幼粒细胞异常增生，这些细胞处于髓系发育的中间阶段^［66］。类似地，CEBPA突变的AML多见于M1或M2型，主要表现为原始粒细胞的异常增殖^［69］。Francois等人^［70］通过分析AML患者白血病细胞的免疫表型特征，提出了SLA（stage of leukemia arrest）分类方法，精确界定了CEBPA突变AML细胞分化受阻的具体阶段，发现这些细胞多处于相对成熟的GMP（粒细胞-单核细胞祖细胞）阶段，且对化疗药物的敏感性较干祖细胞阶段的AML细胞更高。利用Hi-C和ATAC测序技术，Adamo等人^［71］进一步证实了CEBPA双等位基因突变AML细胞处于髓系祖细胞的部分分化状态，并揭示了突变后的CEBPA蛋白仍能与其他CEBP蛋白或髓系分化相关转录因子如RUNX1、AP-1蛋白在染色质上共定位，共享类似的DNA结合位点，这预示着CEBPA双等位基因突变AML细胞仍保留有一定的髓系分化潜能。基于上述发现，一个引人深思的问题是：“CEBPA突变的AML细胞是否能像APL细胞那样，对药物诱导的分化治疗产生积极响应？”Adam等人^［72］研究为此提供了积极线索，他们发现HDAC抑制剂Trichostatin A和伏立诺他能够有效激活CEBPA双等位基因突变AML细胞中粒细胞分化相关基因的表达，成功诱导AML细胞向粒细胞分化。此外，JAK和LSD1抑制剂在抑制细胞增殖的同时，也均展现出了促进CEBPA双等位基因突变AML细胞再分化能力^［65］。综上所述，探索能够诱导CEBPA突变AML细胞分化的药物或分子靶标，或许能为ML治疗开辟一条比传统化疗更为高效、安全的新途径。

5 总结与展望

尽管CEBPA bZIP框内突变已被确立为AML预后良好的分子标志物，目前临床中尚缺乏针对此类患者的精准治疗药物，且传统化疗方案因患者携带CEBPA bZIP框内突变位点及其他共突变基因谱的高度异质性而面临复发风险^［6］。因此，未来的研究应聚集于深入剖析CEBPA bZIP框内突变的具体特征，如突变位点的分布、氨基酸数目的变化数量及性质改变等，并探索这些突变与AML患者临床特征、治疗反应及预后之间的关联性，以期实现对该类突变的精确分类，进而推动个体化治疗策略的发展。

更为重要的是，以往研究揭示了CEBPA双等位基因突变中，截短型CEBPA 蛋白（P30）在维持髓系分化及AML起始中的关键作用。然而，单位点CEBPA bZIP框内突变AML患者临床分子特征与双等位基因突变患者相似，表明无论P30是否表达，CEBPA bZIP框内突变本身即独立驱动AML的发生。这一发现提示，不同CEBPA bZIP突变蛋白的致病潜力及分子致病机制相较于P30蛋白更为复杂且值得深入探讨。传统观点认为，CEBPA bZIP框内突变主要通过影响蛋白稳定性或削弱其DNA结合能力来干扰正常功能^{［25，45］}，进而阻碍髓系分化。然而，鉴于这些突变蛋白保留了完整的N端转录激活结构域，它们是否可能激活特定的促癌基因表达成为新的研究焦点。此外，这些突变可能通过直接干扰DNA结合、调控蛋白翻译后修饰、破坏与其他调节因子的相互作用等多种方式，导致其生物学功能的改变。探索这些不同作用方式背后的共同分子靶标及是否存在普遍适用的作用机制，对于理解CEBPA bZIP突变在AML中的具体作用至关重要。随着三维基因组测序、蛋白结构预测解析、高分辨显微成像及CRISPR/Cas系统介导的高通量筛选技术的飞速发展，我们有望更深入地揭示AML相关bZIP突变蛋白的生物学功能变化，并精准鉴定其致病性的关键分子靶标。这些研究成果将为开发针对CEBPA bZIP突变AML的新型治疗药物、靶点及治疗方案奠定坚实基础，推动AML治疗领域的进一步突破。

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3、NEWELL%E2%80%83L%E2%80%83F%EF%BC%8CCOOK%E2%80%83R%E2%80%83J%EF%BC%8EAdvances%E2%80%83%20in%E2%80%83%20acute%E2%80%83%0Amyeloid%E2%80%83leukemia%EF%BC%BBJ%EF%BC%BD%EF%BC%8EBMJ%EF%BC%8C2021%EF%BC%88375%EF%BC%89%EF%BC%9A%0An2026%EF%BC%8E

4、BHANSALI%E2%80%83R%E2%80%83S%EF%BC%8CPRATZ%E2%80%83K%E2%80%83W%EF%BC%8CLAI%E2%80%83C%EF%BC%8ERecent%E2%80%83%0Aadvances%E2%80%83%20in%E2%80%83%20targeted%E2%80%83%20therapies%E2%80%83%20in%E2%80%83%20acute%E2%80%83%20myeloid%E2%80%83%0Aleukemia%EF%BC%BBJ%EF%BC%BD%EF%BC%8EJ%E2%80%83Hematol%E2%80%83Oncol%EF%BC%8C2023%EF%BC%8C16%EF%BC%881%EF%BC%89%EF%BC%9A%0A29%EF%BC%8E

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7、SU%E2%80%83L%EF%BC%8CGAO%E2%80%83S%E2%80%83J%EF%BC%8CLIU%E2%80%83X%E2%80%83L%EF%BC%8Cet%E2%80%83al%EF%BC%8ECEBPA%E2%80%83mutations%E2%80%83%0Ain%E2%80%83patients%E2%80%83with%E2%80%83de%E2%80%83novo%E2%80%83acute%E2%80%83myeloid%E2%80%83leukemia%EF%BC%9Adata%E2%80%83%0Aanalysis%E2%80%83in%E2%80%83a%E2%80%83Chinese%E2%80%83population%EF%BC%BBJ%EF%BC%BD%EF%BC%8EOnco%E2%80%83Targets%E2%80%83%0ATher%EF%BC%8C2016%EF%BC%889%EF%BC%89%EF%BC%9A3399%E2%80%933403%EF%BC%8E

8、SCHMIDT%E2%80%83L%EF%BC%8CHEYES%E2%80%83E%EF%BC%8CGREBIEN%E2%80%83F%EF%BC%8EGain-of%02Function%E2%80%83Effects%E2%80%83of%E2%80%83N-Terminal%E2%80%83CEBPA%E2%80%83Mutations%E2%80%83in%E2%80%83%0AAcute%E2%80%83Myeloid%E2%80%83Leukemia%EF%BC%BBJ%EF%BC%BD%EF%BC%8EBioessays%EF%BC%8C2020%EF%BC%8C%0A42%EF%BC%882%EF%BC%89%EF%BC%9Ae1900178%EF%BC%8E

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10、WILHELMSON%E2%80%83A%E2%80%83S%EF%BC%8CPORSE%E2%80%83B%E2%80%83T%EF%BC%8ECCAAT%E2%80%83enhancer%E2%80%83%0Abinding%E2%80%83protein%E2%80%83alpha%EF%BC%88CEBPA%EF%BC%89biallelic%E2%80%83%20acute%E2%80%83%0Amyeloid%E2%80%83leukaemia%EF%BC%9Acooperating%E2%80%83lesions%EF%BC%8Cmolecular%E2%80%83%0Amechanisms%E2%80%83and%E2%80%83clinical%E2%80%83relevance%EF%BC%BBJ%EF%BC%BD%EF%BC%8EBr%E2%80%83%20J%E2%80%83%0AHaematol%EF%BC%8C2020%EF%BC%8C190%EF%BC%884%EF%BC%89%EF%BC%9A495-507%EF%BC%8E

11、ARBER%E2%80%83D%E2%80%83A%EF%BC%8CORAZI%E2%80%83A%EF%BC%8CHASSERJIAN%E2%80%83R%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0AThe%E2%80%83%202016%E2%80%83%20revision%E2%80%83to%E2%80%83the%E2%80%83World%E2%80%83Health%E2%80%83Organization%E2%80%83%0Aclassification%E2%80%83of%E2%80%83myeloid%E2%80%83neoplasms%E2%80%83and%E2%80%83acute%E2%80%83leukemia%0A%EF%BC%BBJ%EF%BC%BD%EF%BC%8EBlood%EF%BC%8C2016%EF%BC%8C127%EF%BC%8820%EF%BC%89%EF%BC%9A2391-2405%EF%BC%8E

12、WAKITA%E2%80%83S%EF%BC%8CSAKAGUCHI%E2%80%83M%EF%BC%8COH%E2%80%83I%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0APrognostic%E2%80%83impact%E2%80%83of%E2%80%83CEBPA%E2%80%83bZIP%E2%80%83domain%E2%80%83mutation%E2%80%83in%E2%80%83%0Aacute%E2%80%83myeloid%E2%80%83leukemia%EF%BC%BBJ%EF%BC%BD%EF%BC%8EBlood%E2%80%83Adv%EF%BC%8C2022%EF%BC%8C6%0A%EF%BC%881%EF%BC%89%EF%BC%9A238-247%EF%BC%8E

13、HUBER%E2%80%83S%EF%BC%8CBAER%E2%80%83C%EF%BC%8CHUTTER%E2%80%83S%EF%BC%8Cet%E2%80%83al%EF%BC%8EAML%E2%80%83%0Aclassification%E2%80%83in%E2%80%83the%E2%80%83year%E2%80%832023%EF%BC%9AHow%E2%80%83%20to%E2%80%83%20avoid%E2%80%83%20a%E2%80%83%0ABabylonian%E2%80%83confusion%E2%80%83of%E2%80%83languages%EF%BC%BBJ%EF%BC%BD%EF%BC%8ELeukemia%EF%BC%8C%0A2023%EF%BC%8C37%EF%BC%887%EF%BC%89%EF%BC%9A1413-1420%EF%BC%8E

14、FRIEDMAN%E2%80%83A%E2%80%83D%EF%BC%8EC%2FEBP%CE%B1%E2%80%83in%E2%80%83normal%E2%80%83and%E2%80%83malignant%E2%80%83%0Amyelopoiesis%EF%BC%BBJ%EF%BC%BD%EF%BC%8EInt%E2%80%83J%E2%80%83Hematol%EF%BC%8C2015%EF%BC%8C101%0A%EF%BC%884%EF%BC%89%EF%BC%9A330-341%EF%BC%8E

15、%E2%80%83%20IN%E2%80%83K%EF%BC%8CZAINI%E2%80%83M%E2%80%83A%EF%BC%8CM%C3%9CLLER%E2%80%83C%EF%BC%8Cet%E2%80%83al%EF%BC%8EShwachman%02Bodian-Diamond%E2%80%83syndrome%EF%BC%88SBDS%EF%BC%89p%20r%20ot%20ei%20n%E2%80%83%0Adeficiency%E2%80%83impairs%E2%80%83translation%E2%80%83re-initiation%E2%80%83from%E2%80%83C%2F%0AEBP%CE%B1%E2%80%83and%E2%80%83C%2FEBP%CE%B2%E2%80%83mRNAs%EF%BC%BBJ%EF%BC%BD%EF%BC%8ENucleic%E2%80%83Acids%E2%80%83%0ARes%EF%BC%8C2016%EF%BC%8C44%EF%BC%889%EF%BC%89%EF%BC%9A4134-4146%EF%BC%8E

16、%E2%80%83%20RAMJI%E2%80%83DP%EF%BC%8CFOKA%E2%80%83P%EF%BC%8ECCAAT%2Fenhancer-binding%E2%80%83%0Aproteins%EF%BC%9Astructure%EF%BC%8Cfunction%E2%80%83and%E2%80%83regulation%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0ABiochem%E2%80%83J%EF%BC%8C2002%EF%BC%8C365%EF%BC%88Pt%E2%80%833%EF%BC%89%EF%BC%9A561-575%EF%BC%8E

17、MILLER%E2%80%83M%EF%BC%8CSHUMAN%E2%80%83J%E2%80%83D%EF%BC%8CSEBASTIAN%E2%80%83T%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0AStructural%E2%80%83basis%E2%80%83for%E2%80%83DNA%E2%80%83recognition%E2%80%83by%E2%80%83the%E2%80%83basic%E2%80%83region%E2%80%83%0Aleucine%E2%80%83zipper%E2%80%83transcription%E2%80%83factor%E2%80%83CCAAT%2Fenhancer%02binding%E2%80%83protein%E2%80%83%CE%B1%EF%BC%BBJ%EF%BC%BD%EF%BC%8EJ%E2%80%83Biol%E2%80%83Chem%EF%BC%8C2003%EF%BC%8C278%0A%EF%BC%8817%EF%BC%89%EF%BC%9A15178-15184%EF%BC%8E

18、GARCIA-CUELLAR%E2%80%83M%E2%80%83P%EF%BC%8CAKAN%E2%80%83S%EF%BC%8CSLANY%E2%80%83R%E2%80%83K%EF%BC%8E%0AA%E2%80%83C%2Febp%CE%B1%E2%80%83isoform%E2%80%83specific%E2%80%83differentiation%E2%80%83program%E2%80%83in%E2%80%83%0Aimmortalized%E2%80%83myelocytes%EF%BC%BBJ%EF%BC%BD%EF%BC%8ELeukemia%EF%BC%8C2023%EF%BC%8C37%0A%EF%BC%889%EF%BC%89%EF%BC%9A1850-1859%EF%BC%8E

19、VINSON%E2%80%83C%E2%80%83R%EF%BC%8CHAI%E2%80%83T%EF%BC%8CBOYD%E2%80%83S%E2%80%83M%EF%BC%8EDimerization%E2%80%83%0Aspecificity%E2%80%83of%E2%80%83the%E2%80%83leucine%E2%80%83zipper-containing%E2%80%83bZIP%E2%80%83motif%E2%80%83%0Aon%E2%80%83DNA%E2%80%83binding%EF%BC%9Aprediction%E2%80%83and%E2%80%83rational%E2%80%83design%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0AGenes%E2%80%83Dev%EF%BC%8C1993%EF%BC%8C7%EF%BC%886%EF%BC%89%EF%BC%9A1047-1058%EF%BC%8E

20、ZHANG%E2%80%83D%E2%80%83E%EF%BC%8CZHANG%E2%80%83P%EF%BC%8CWANG%E2%80%83N%E2%80%83D%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0AAbsence%E2%80%83%20of%E2%80%83%20granulocyte%E2%80%83%20colony-stimulating%E2%80%83factor%E2%80%83%0Asignaling%E2%80%83%20and%E2%80%83%20neutrophil%E2%80%83%20development%E2%80%83in%E2%80%83%20CCAAT%E2%80%83%0Aenhancer%E2%80%83binding%E2%80%83protein%E2%80%83%CE%B1-deficient%E2%80%83mice%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0AProc%E2%80%83Natl%E2%80%83Acad%E2%80%83Sci%E2%80%83U%E2%80%83S%E2%80%83A%EF%BC%8C1997%EF%BC%8C94%EF%BC%882%EF%BC%89%EF%BC%9A569-574%EF%BC%8E

21、%E2%80%83%20SCHUSTER%E2%80%83M%E2%80%83B%EF%BC%8CFRANK%E2%80%83A%E2%80%83K%EF%BC%8CBAGGER%E2%80%83F%E2%80%83O%EF%BC%8C%0Aet%E2%80%83al%EF%BC%8ELack%E2%80%83of%E2%80%83the%E2%80%83p42%E2%80%83form%E2%80%83of%E2%80%83C%2FEBP%CE%B1%E2%80%83leads%E2%80%83to%E2%80%83%0Aspontaneous%E2%80%83immortalization%E2%80%83and%E2%80%83lineage%E2%80%83infidelity%E2%80%83of%E2%80%83%0Acommitted%E2%80%83myeloid%E2%80%83progenitors%EF%BC%BBJ%EF%BC%BD%EF%BC%8EExp%E2%80%83Hematol%EF%BC%8C%0A2013%EF%BC%8C41%EF%BC%8810%EF%BC%89%EF%BC%9A882-893%EF%BC%8Ee16%EF%BC%8E

22、ZHANG%E2%80%83P%EF%BC%8CIWASAKI-ARAI%E2%80%83J%EF%BC%8CIWASAKI%E2%80%83H%EF%BC%8C%0Aet%E2%80%83al%EF%BC%8EEnhancement%E2%80%83%20of%E2%80%83%20hematopoietic%E2%80%83%20stem%E2%80%83%20cell%E2%80%83%0Arepopulating%E2%80%83capacity%E2%80%83and%E2%80%83self-renewal%E2%80%83in%E2%80%83the%E2%80%83absence%E2%80%83%0Aof%E2%80%83the%E2%80%83transcription%E2%80%83factor%E2%80%83C%2FEBP%CE%B1%EF%BC%BBJ%EF%BC%BD%EF%BC%8EImmunity%EF%BC%8C%0A2004%EF%BC%8C21%EF%BC%886%EF%BC%89%EF%BC%9A853-863%EF%BC%8E

23、%E2%80%83%20DAI%E2%80%83Y%E2%80%83M%EF%BC%8CZHU%E2%80%83L%EF%BC%8CHUANG%E2%80%83Z%E2%80%83B%EF%BC%8Cet%E2%80%83al%EF%BC%8ECebp%CE%B1%0Ais%E2%80%83essential%E2%80%83for%E2%80%83the%E2%80%83embryonic%E2%80%83myeloid%E2%80%83progenitor%E2%80%83and%E2%80%83%0Aneutrophil%E2%80%83maintenance%E2%80%83in%E2%80%83zebrafish%EF%BC%BBJ%EF%BC%BD%EF%BC%8EJ%E2%80%83Genet%E2%80%83%0AGenomics%EF%BC%8C2016%EF%BC%8C43%EF%BC%8810%EF%BC%89%EF%BC%9A593-600%EF%BC%8E

24、OHLSSON%E2%80%83E%EF%BC%8CSCHUSTER%E2%80%83M%E2%80%83B%EF%BC%8CHASEMANN%E2%80%83M%EF%BC%8Cet%E2%80%83%0Aal%EF%BC%8EThe%E2%80%83multifaceted%E2%80%83functions%E2%80%83of%E2%80%83C%2FEBP%CE%B1%E2%80%83in%E2%80%83normal%E2%80%83%0Aand%E2%80%83malignant%E2%80%83haematopoiesis%EF%BC%BBJ%EF%BC%BD%EF%BC%8ELeukemia%EF%BC%8C%0A2016%EF%BC%8C30%EF%BC%884%EF%BC%89%EF%BC%9A767-775%EF%BC%8E

25、AVELLINO%E2%80%83R%EF%BC%8CDELWEL%E2%80%83R%EF%BC%8EEx%20p%20re%20s%20sio%20n%E2%80%83%20a%20n%20d%E2%80%83%0Aregulation%E2%80%83of%E2%80%83C%2FEBP%CE%B1%E2%80%83in%E2%80%83normal%E2%80%83myelopoiesis%E2%80%83and%E2%80%83in%E2%80%83%0Amalignant%E2%80%83transformation%EF%BC%BBJ%EF%BC%BD%EF%BC%8EBlood%EF%BC%8C2017%EF%BC%8C129%0A%EF%BC%8815%EF%BC%89%EF%BC%9A2083-2091%EF%BC%8E

26、%E2%80%83%20JOHNSON%E2%80%83P%E2%80%83F%EF%BC%8EMolecular%E2%80%83stop%E2%80%83signs%EF%BC%9Aregulation%E2%80%83of%E2%80%83%0Acell-cycle%E2%80%83arrest%E2%80%83by%E2%80%83C%2FEBP%E2%80%83transcription%E2%80%83factors%EF%BC%BBJ%EF%BC%BD%EF%BC%8EJ%E2%80%83%0ACell%E2%80%83Sci%EF%BC%8C2005%EF%BC%8C118%EF%BC%88Pt%E2%80%8312%EF%BC%89%EF%BC%9A2545-2555%EF%BC%8E

27、YUAN%E2%80%83H%EF%BC%8CGAO%E2%80%83S%EF%BC%8CCHEN%E2%80%83H%EF%BC%8Cet%E2%80%83al%EF%BC%8EPrimitive%E2%80%83%0Amacrophages%E2%80%83are%E2%80%83%20dispensable%E2%80%83for%E2%80%83HSPC%E2%80%83mobilization%E2%80%83%0Aand%E2%80%83definitive%E2%80%83hematopoiesis%EF%BC%BBJ%EF%BC%BD%EF%BC%8EBlood%EF%BC%8C2019%EF%BC%8C%0A134%EF%BC%889%EF%BC%89%EF%BC%9A782-784%EF%BC%8E

28、CHEN%E2%80%83K%E2%80%83M%EF%BC%8CWU%E2%80%83J%E2%80%83Y%EF%BC%8CZHANG%E2%80%83Y%E2%80%83X%EF%BC%8Cet%E2%80%83al%EF%BC%8ECebpa%E2%80%83%0Ais%E2%80%83required%E2%80%83for%E2%80%83haematopoietic%E2%80%83stem%E2%80%83and%E2%80%83progenitor%E2%80%83cell%E2%80%83%0Ageneration%E2%80%83and%E2%80%83maintenance%E2%80%83in%E2%80%83zebrafish%EF%BC%BBJ%EF%BC%BD%EF%BC%8EOpen%E2%80%83%0ABiol%EF%BC%8C2024%EF%BC%8C14%EF%BC%8811%EF%BC%89%EF%BC%9A240215%EF%BC%8E

29、%E2%80%83LIN%E2%80%83L%E2%80%83I%20%EF%BC%8C%20CHEN%E2%80%83C%E2%80%83Y%20%EF%BC%8C%20LIN%E2%80%83D%E2%80%83T%20%EF%BC%8C%20et%E2%80%83al%20%EF%BC%8E%0ACharacterization%E2%80%83%20of%E2%80%83%20CEBPA%E2%80%83%20mutations%E2%80%83%20in%E2%80%83%20acute%E2%80%83%0Amyeloid%E2%80%83leukemia%EF%BC%9Amost%E2%80%83%20patients%E2%80%83%20with%E2%80%83%20CEBPA%E2%80%83%0Amutations%E2%80%83have%E2%80%83biallelic%E2%80%83mutations%E2%80%83and%E2%80%83show%E2%80%83a%E2%80%83distinct%E2%80%83%0Aimmunophenotype%E2%80%83of%E2%80%83the%E2%80%83leukemic%E2%80%83cells%EF%BC%BBJ%EF%BC%BD%EF%BC%8EClin%E2%80%83%0ACancer%E2%80%83Res%EF%BC%8C2005%EF%BC%8C11%EF%BC%884%EF%BC%89%EF%BC%9A1372-1379%EF%BC%8E

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48、GENTLE%E2%80%83I%E2%80%83E%EF%BC%8CMOELTER%E2%80%83I%EF%BC%8CBADR%E2%80%83M%E2%80%83T%EF%BC%8Cet%E2%80%83al%EF%BC%8EThe%E2%80%83%0AAML-associated%E2%80%83K313%E2%80%83mutation%E2%80%83enhances%E2%80%83C%2FEBP%CE%B1%0Aactivity%E2%80%83by%E2%80%83leading%E2%80%83to%E2%80%83C%2FEBP%CE%B1%E2%80%83overexpression%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0ACell%E2%80%83Death%E2%80%83Dis%EF%BC%8C2021%EF%BC%8C12%EF%BC%887%EF%BC%89%EF%BC%9A675%EF%BC%8E

49、BARARIA%E2%80%83D%EF%BC%8CKWOK%E2%80%83H%E2%80%83S%EF%BC%8CWELNER%E2%80%83R%E2%80%83S%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0AAcetylation%E2%80%83of%E2%80%83C%2FEBP%CE%B1%E2%80%83inhibits%E2%80%83its%E2%80%83%20granulopoietic%E2%80%83%0Afunction%EF%BC%BBJ%EF%BC%BD%EF%BC%8ENat%E2%80%83Commun%EF%BC%8C2016%EF%BC%887%EF%BC%89%EF%BC%9A10968%EF%BC%8E

50、%E2%80%83%20CHEN%E2%80%83X%EF%BC%8CZHOU%E2%80%83W%EF%BC%8CSONG%E2%80%83R%E2%80%83H%EF%BC%8Cet%E2%80%83al%EF%BC%8ETumor%E2%80%83%0Asuppressor%E2%80%83CEBPA%E2%80%83interacts%E2%80%83with%E2%80%83and%E2%80%83inhibits%E2%80%83DNMT3A%E2%80%83%0Aactivity%EF%BC%BBJ%EF%BC%BD%EF%BC%8ESci%E2%80%83Adv%EF%BC%8C2022%EF%BC%8C8%EF%BC%884%EF%BC%89%EF%BC%9Aeabl5220%EF%BC%8E

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54、KUROSAWA%E2%80%83S%EF%BC%8CYAMAGUCHI%E2%80%83H%EF%BC%8CYAMAGUCHI%E2%80%83%0AT%EF%BC%8Cet%E2%80%83al%EF%BC%8EThe%E2%80%83prognostic%E2%80%83impact%E2%80%83of%E2%80%83FLT3-ITD%EF%BC%8CNPM1%E2%80%83%0Aand%E2%80%83CEBPa%E2%80%83in%E2%80%83cytogenetically%E2%80%83intermediate-risk%E2%80%83AML%E2%80%83%0Aafter%E2%80%83first%E2%80%83relapse%EF%BC%BBJ%EF%BC%BD%EF%BC%8EInt%E2%80%83J%E2%80%83Hematol%EF%BC%8C2020%EF%BC%8C112%0A%EF%BC%882%EF%BC%89%EF%BC%9A200-209%EF%BC%8E%0A

55、AHN%E2%80%83J%E2%80%83S%EF%BC%8CKIM%E2%80%83J%E2%80%83Y%EF%BC%8CKIM%E2%80%83H%E2%80%83J%EF%BC%8Cet%E2%80%83al%EF%BC%8ENormal%E2%80%83%0Akaryotype%E2%80%83acute%E2%80%83myeloid%E2%80%83leukemia%E2%80%83patients%E2%80%83with%E2%80%83CEBPA%E2%80%83%0Adouble%E2%80%83mutation%E2%80%83%20have%E2%80%83%20a%E2%80%83favorable%E2%80%83%20prognosis%E2%80%83%20but%E2%80%83%20no%E2%80%83%0Asurvival%E2%80%83benefit%E2%80%83from%E2%80%83allogeneic%E2%80%83stem%E2%80%83cell%E2%80%83transplant%0A%EF%BC%BBJ%EF%BC%BD%EF%BC%8EAnn%E2%80%83Hematol%EF%BC%8C2016%EF%BC%8C95%EF%BC%882%EF%BC%89%EF%BC%9A301-310%EF%BC%8E

56、SU%E2%80%83L%EF%BC%8CGAO%E2%80%83S%E2%80%83J%EF%BC%8CTAN%E2%80%83Y%E2%80%83H%EF%BC%8Cet%E2%80%83al%EF%BC%8ECSF3R%E2%80%83mutations%E2%80%83%0Awere%E2%80%83%20associated%E2%80%83%20with%E2%80%83%20an%E2%80%83%20unfavorable%E2%80%83%20prognosis%E2%80%83in%E2%80%83%0Apatients%E2%80%83with%E2%80%83%20acute%E2%80%83myeloid%E2%80%83leukemia%E2%80%83with%E2%80%83CEBPA%E2%80%83%0Adouble%E2%80%83mutations%EF%BC%BBJ%EF%BC%BD%EF%BC%8EAnn%E2%80%83Hematol%EF%BC%8C2019%EF%BC%8C98%0A%EF%BC%887%EF%BC%89%EF%BC%9A1641-1646%EF%BC%8E

57、TIEN%E2%80%83F%E2%80%83M%EF%BC%8CYAO%E2%80%83C%E2%80%83Y%EF%BC%8CTSAI%E2%80%83X%E2%80%83C%E2%80%83H%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0ADysregulated%E2%80%83immune%E2%80%83%20and%E2%80%83%20metabolic%E2%80%83%20pathways%E2%80%83%20are%E2%80%83%0Aassociated%E2%80%83with%E2%80%83%20poor%E2%80%83%20survival%E2%80%83in%E2%80%83adult%E2%80%83acute%E2%80%83myeloid%E2%80%83%0Aleukemia%E2%80%83with%E2%80%83CEBPA%E2%80%83bZIP%E2%80%83in-frame%E2%80%83mutations%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0ABlood%E2%80%83Cancer%E2%80%83J%EF%BC%8C2024%EF%BC%8C14%EF%BC%881%EF%BC%89%EF%BC%9A15%EF%BC%8E

58、WANG%E2%80%83J%EF%BC%8CLU%E2%80%83R%E2%80%83Q%EF%BC%8CWU%E2%80%83Y%EF%BC%8Cet%E2%80%83al%EF%BC%8EDetection%E2%80%83of%E2%80%83%20measurable%E2%80%83%20residual%E2%80%83%20disease%E2%80%83%20may%E2%80%83%20better%E2%80%83%20predict%E2%80%83%0Aoutcomes%E2%80%83than%E2%80%83mutations%E2%80%83%20based%E2%80%83%20on%E2%80%83%20next-generation%E2%80%83%0Asequencing%E2%80%83in%E2%80%83acute%E2%80%83myeloid%E2%80%83leukaemia%E2%80%83with%E2%80%83biallelic%E2%80%83%0Amutations%E2%80%83of%E2%80%83CEBPA%EF%BC%BBJ%EF%BC%BD%EF%BC%8EBr%E2%80%83J%E2%80%83Haematol%EF%BC%8C2020%EF%BC%8C%0A190%EF%BC%884%EF%BC%89%EF%BC%9A533-544%EF%BC%8E

59、%E2%80%83%20WANG%E2%80%83J%EF%BC%8CJIANG%E2%80%83H%EF%BC%8CJING%E2%80%83Y%EF%BC%8Cet%E2%80%83al%EF%BC%8EPrognostic%E2%80%83%0Aimplications%E2%80%83of%E2%80%83the%E2%80%83%20detection%E2%80%83of%E2%80%83measurable%E2%80%83%20residual%E2%80%83%0Adisease%E2%80%83%20and%E2%80%83%20mutations%E2%80%83%20based%E2%80%83%20on%E2%80%83%20next-generation%E2%80%83%0Asequencing%E2%80%83in%E2%80%83acute%E2%80%83myeloid%E2%80%83leukaemia%E2%80%83with%E2%80%83biallelic%E2%80%83%0Amutations%E2%80%83of%E2%80%83CEBPA%EF%BC%BBJ%EF%BC%BD%EF%BC%8EBr%E2%80%83J%E2%80%83Haematol%EF%BC%8C2022%EF%BC%8C%0A198%EF%BC%881%EF%BC%89%EF%BC%9Ae3-e8%EF%BC%8E

60、D%C3%96HNER%E2%80%83H%EF%BC%8CWEI%E2%80%83A%E2%80%83H%EF%BC%8CAPPELBAUM%E2%80%83F%E2%80%83R%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0ADiagnosis%E2%80%83and%E2%80%83management%E2%80%83of%E2%80%83AML%E2%80%83in%E2%80%83adults%EF%BC%9A2022%E2%80%83%0Arecommendations%E2%80%83from%E2%80%83an%E2%80%83international%E2%80%83expert%E2%80%83panel%E2%80%83on%E2%80%83%0Abehalf%E2%80%83of%E2%80%83the%E2%80%83ELN%EF%BC%BBJ%EF%BC%BD%EF%BC%8EBlood%EF%BC%8C2022%EF%BC%8C140%EF%BC%8812%EF%BC%89%EF%BC%9A%0A1345-1377%EF%BC%8E

61、%E2%80%83ARSLAN%E2%80%83S%EF%BC%8CZHANG%E2%80%83J%EF%BC%8CDHAKAL%E2%80%83P%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0AOutcomes%E2%80%83of%E2%80%83therapy%E2%80%83with%E2%80%83venetoclax%E2%80%83combined%E2%80%83with%E2%80%83a%E2%80%83%0Ahypomethylating%E2%80%83agent%E2%80%83in%E2%80%83favorable-risk%E2%80%83acute%E2%80%83myeloid%E2%80%83%0Aleukemia%EF%BC%BBJ%EF%BC%BD%EF%BC%8EAm%E2%80%83J%E2%80%83Hematol%EF%BC%8C2021%EF%BC%8C96%EF%BC%883%EF%BC%89%EF%BC%9A%0AE59-E63%EF%BC%8E

62、%E2%80%83%20ZHANG%E2%80%83H%EF%BC%8CALBERICH-JORDA%E2%80%83M%EF%BC%8CAMABILE%E2%80%83%0AG%EF%BC%8Cet%E2%80%83al%EF%BC%8ESox4%E2%80%83is%E2%80%83a%E2%80%83key%E2%80%83oncogenic%E2%80%83target%E2%80%83in%E2%80%83C%2FEBP%CE%B1%0Amutant%E2%80%83acute%E2%80%83myeloid%E2%80%83leukemia%EF%BC%BBJ%EF%BC%BD%EF%BC%8ECancer%E2%80%83Cell%EF%BC%8C%0A2013%EF%BC%8C24%EF%BC%885%EF%BC%89%EF%BC%9A575-588%EF%BC%8E

63、%E2%80%83%20SCHMIDT%E2%80%83L%EF%BC%8CHEYES%E2%80%83E%EF%BC%8CSCHEIBLECKER%E2%80%83L%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0ACEBPA-mutated%E2%80%83leukemia%E2%80%83is%E2%80%83sensitive%E2%80%83to%E2%80%83genetic%E2%80%83and%E2%80%83%0Apharmacological%E2%80%83targeting%E2%80%83of%E2%80%83the%E2%80%83MLL1%E2%80%83complex%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0ALeukemia%EF%BC%8C2019%EF%BC%8C33%EF%BC%887%EF%BC%89%EF%BC%9A1608-1619%EF%BC%8E

64、LAVAL%C3%8D%E2%80%83V-P%EF%BC%8CKROSL%E2%80%83J%EF%BC%8CLEMIEUX%E2%80%83S%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0AChemo-genomic%E2%80%83interrogation%E2%80%83%20of%E2%80%83%20CEBPA%E2%80%83%20mutated%E2%80%83%0AAML%E2%80%83reveals%E2%80%83recurrent%E2%80%83CSF3R%E2%80%83mutations%E2%80%83and%E2%80%83subgroup%E2%80%83%0Asensitivity%E2%80%83to%E2%80%83JAK%E2%80%83inhibitors%EF%BC%BBJ%EF%BC%BD%EF%BC%8EBlood%EF%BC%8C2016%EF%BC%8C%0A127%EF%BC%8824%EF%BC%89%EF%BC%9A3054-3061%EF%BC%8E

65、%E2%80%83%20BRAUN%E2%80%83T%E2%80%83P%EF%BC%8CCOBLENTZ%E2%80%83C%EF%BC%8CDANIEL%E2%80%83J%E2%80%83COLEMAN%E2%80%83%0AB%E2%80%83M%EF%BC%8Cet%E2%80%83al%EF%BC%8ECombined%E2%80%83%20inhibition%E2%80%83%20of%E2%80%83%20JAK%2FSTAT%E2%80%83%0Apathway%E2%80%83%20and%E2%80%83%20lysine-specific%E2%80%83%20demethylase%E2%80%83%201%E2%80%83%20as%E2%80%83%20a%E2%80%83therapeutic%E2%80%83%20strategy%E2%80%83in%E2%80%83CSF3R%2FCEBPA%E2%80%83mutant%E2%80%83acute%E2%80%83%0Amyeloid%E2%80%83leukemia%EF%BC%BBJ%EF%BC%BD%EF%BC%8EProc%E2%80%83Natl%E2%80%83Acad%E2%80%83Sci%E2%80%83U%E2%80%83S%E2%80%83A%EF%BC%8C%0A2020%EF%BC%8C117%EF%BC%8824%EF%BC%89%EF%BC%9A13670-13679%EF%BC%8E

66、LO-COCO%E2%80%83F%EF%BC%8CAVVISATI%E2%80%83G%EF%BC%8CVIGNETTI%E2%80%83M%EF%BC%8C%0Aet%E2%80%83al%EF%BC%8ERetinoic%E2%80%83%20acid%E2%80%83%20and%E2%80%83%20arsenic%E2%80%83trioxide%E2%80%83for%E2%80%83%20acute%E2%80%83%0Apromyelocytic%E2%80%83leukemia%EF%BC%BBJ%EF%BC%BD%EF%BC%8EN%E2%80%83Engl%E2%80%83J%E2%80%83Med%EF%BC%8C2013%EF%BC%8C%0A369%EF%BC%882%EF%BC%89%EF%BC%9A111-121%EF%BC%8E

67、NI%E2%80%83X%EF%BC%8CHU%E2%80%83G%EF%BC%8CCAI%E2%80%83X%EF%BC%8EThe%E2%80%83success%E2%80%83and%E2%80%83the%E2%80%83challenge%E2%80%83of%E2%80%83%0Aall-trans%E2%80%83retinoic%E2%80%83acid%E2%80%83in%E2%80%83the%E2%80%83treatment%E2%80%83of%E2%80%83cancer%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0ACrit%E2%80%83Rev%E2%80%83Food%E2%80%83Sci%E2%80%83Nutr%EF%BC%8C2019%EF%BC%8C59%EF%BC%88sup1%EF%BC%89%EF%BC%9A%0AS71-S80%EF%BC%8E

68、NGUYEN%E2%80%83C%E2%80%83H%EF%BC%8CGRANDITS%E2%80%83A%E2%80%83M%EF%BC%8CPURTON%E2%80%83L%E2%80%83E%EF%BC%8Cet%E2%80%83%0Aal%EF%BC%8EAll-trans%E2%80%83retinoic%E2%80%83acid%E2%80%83in%E2%80%83non-promyelocytic%E2%80%83acute%E2%80%83%0Amyeloid%E2%80%83leukemia%EF%BC%9Adriver%E2%80%83lesion%E2%80%83dependent%E2%80%83effects%E2%80%83on%E2%80%83%0Aleukemic%E2%80%83stem%E2%80%83cells%EF%BC%BBJ%EF%BC%BD%EF%BC%8ECell%E2%80%83Cycle%EF%BC%8C2020%EF%BC%8C19%0A%EF%BC%8820%EF%BC%89%EF%BC%9A2573-2588%EF%BC%8E

69、SNADDON%E2%80%83J%EF%BC%8CSMITH%E2%80%83M%E2%80%83L%EF%BC%8CNEAT%E2%80%83M%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0AMutations%E2%80%83%20of%E2%80%83%20CEBPA%E2%80%83%20in%E2%80%83%20acute%E2%80%83%20myeloid%E2%80%83%20leukemia%E2%80%83%0AFAB%E2%80%83types%E2%80%83M1%E2%80%83and%E2%80%83M2%EF%BC%BBJ%EF%BC%BD%EF%BC%8EGenes%E2%80%83Chromosomes%E2%80%83%0ACancer%EF%BC%8C2003%EF%BC%8C37%EF%BC%881%EF%BC%89%EF%BC%9A72-78%EF%BC%8E

70、VERGEZ%E2%80%83F%EF%BC%8CLARGEAUD%E2%80%83L%EF%BC%8CBERTOLI%E2%80%83S%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0APhenotypically-defined%E2%80%83%20stages%E2%80%83%20of%E2%80%83leukemia%E2%80%83%20arrest%E2%80%83%0Apredict%E2%80%83main%E2%80%83driver%E2%80%83mutations%E2%80%83subgroups%EF%BC%8Cand%E2%80%83outcome%E2%80%83%0Ain%E2%80%83acute%E2%80%83myeloid%E2%80%83leukemia%EF%BC%BBJ%EF%BC%BD%EF%BC%8EBlood%E2%80%83Cancer%E2%80%83J%EF%BC%8C%0A2022%EF%BC%8C12%EF%BC%888%EF%BC%89%EF%BC%9A117%EF%BC%8E

71、ADAMO%E2%80%83A%EF%BC%8CCHIN%E2%80%83P%EF%BC%8CKEANE%E2%80%83P%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0AIdentification%E2%80%83and%E2%80%83interrogation%E2%80%83of%E2%80%83the%E2%80%83gene%E2%80%83%20regulatory%E2%80%83%0Anetwork%E2%80%83%20of%E2%80%83%20CEBPA-double%E2%80%83%20mutant%E2%80%83%20acute%E2%80%83%20myeloid%E2%80%83%0Aleukemia%EF%BC%BBJ%EF%BC%BD%EF%BC%8ELeukemia%EF%BC%8C2023%EF%BC%8C37%EF%BC%881%EF%BC%89%EF%BC%9A102-%0A112%EF%BC%8E

72、LISS%E2%80%83A%EF%BC%8COOI%E2%80%83C%E2%80%83H%EF%BC%8CZJABLOVSKAJA%E2%80%83P%EF%BC%8Cet%E2%80%83al%EF%BC%8EThe%E2%80%83%0Agene%E2%80%83%20signature%E2%80%83in%E2%80%83CCAAT-enhancer-binding%E2%80%83%20protein%E2%80%83%0A%CE%B1%E2%80%83%20dysfunctional%E2%80%83%20acute%E2%80%83%20myeloid%E2%80%83leukemia%E2%80%83%20predicts%E2%80%83%0Aresponsiveness%E2%80%83to%E2%80%83histone%E2%80%83deacetylase%E2%80%83inhibitors%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0AHaematologica%EF%BC%8C2014%EF%BC%8C99%EF%BC%884%EF%BC%89%EF%BC%9A697-705.

1、国家重点研发计划项目（2023YFA1800100）()