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Article(id=1198558107002564917, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198558106218230069, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.1579.2024.0418, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1701187200000, receivedDateStr=2023-11-29, revisedDate=null, revisedDateStr=null, acceptedDate=1711036800000, acceptedDateStr=2024-03-22, onlineDate=1763688120842, onlineDateStr=2025-11-21, pubDate=1727452800000, pubDateStr=2024-09-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763688120842, onlineIssueDateStr=2025-11-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763688120842, creator=13701087609, updateTime=1763688120842, updator=13701087609, issue=Issue{id=1198558106218230069, tenantId=1146029695717560320, journalId=1189873630562394117, year='2024', volume='49', issue='9', pageStart='977', pageEnd='1098', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1763688120655, creator=13701087609, updateTime=1763689155065, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1198562444915339352, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198558106218230069, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1198562444915339353, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198558106218230069, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1094, endPage=1098, ext={EN=ArticleExt(id=1198558107820454209, articleId=1198558107002564917, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Research progress on the role and mechanism of IRAK4 in hematological malignancies, columnId=1190243275882729994, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

Interleukin-1 receptor associated kinase 4 (IRAK4) plays a crucial role in signal transduction and regulation in the TLRs/IL-1R signaling pathway, coordinating multiple inflammatory pathways involving immune system activation, cytokine production, and cell proliferation and differentiation. IRAK4 is associated with the pathogenesis and progression of hematological malignancies, including myelodysplastic syndrome, acute myeloid leukemia, chronic lymphocytic leukemia, and lymphoma. Therefore, IRAK4 may serve as an effective therapeutic target for hematologic malignancies. This review summarizes the research advances in the structure and function of IRAK4, as well as its mechanism of action and therapeutic implications in hematological malignancies, aiming to provide insights into pathogenesis of related diseases and targeted therapy research.

, correspAuthors=Lian-Sheng Zhang, authorNote=null, correspAuthorsNote=
E-mail:
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白细胞介素-1受体相关激酶4(IRAK4)在TLRs/IL-1R信号通路中发挥着关键的信号转导及调控作用，协调涉及免疫系统启动、细胞因子产生和细胞增殖与分化的多种炎症途径，与血液系统恶性肿瘤的发病机制和进展有关，包括骨髓增生异常综合征、急性髓系白血病、慢性淋巴细胞白血病和淋巴瘤等疾病。因此，IRAK4可能为血液系统恶性肿瘤的有效治疗靶点。本文就IRAK4的结构和功能及其在血液系统恶性肿瘤中的作用机制和治疗等方面的研究进展进行综述，旨在为揭示相关疾病的发生机制和靶向治疗研究提供参考。

, correspAuthors=张连生, authorNote=null, correspAuthorsNote=
张连生，E-mail：
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商颖，硕士研究生，主要从事血液肿瘤免疫机制方面的研究

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商颖，硕士研究生，主要从事血液肿瘤免疫机制方面的研究

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商颖，硕士研究生，主要从事血液肿瘤免疫机制方面的研究

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IRAK4在血液系统恶性肿瘤中的作用及其机制研究进展
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商颖 , 李莉娟 , 张连生 *
解放军医学杂志 | 综述 2024,49(9): 1094-1098
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解放军医学杂志 | 综述 2024, 49(9): 1094-1098
IRAK4在血液系统恶性肿瘤中的作用及其机制研究进展
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商颖, 李莉娟, 张连生*
作者信息
  • 兰州大学第二医院血液科，甘肃兰州 730030

    • 商颖，硕士研究生，主要从事血液肿瘤免疫机制方面的研究

通讯作者:

张连生，E-mail：
Research progress on the role and mechanism of IRAK4 in hematological malignancies
Ying Shang, Li-Juan Li, Lian-Sheng Zhang*
Affiliations
  • Department of Hematology, the Second Hospital of Lanzhou University, Lanzhou, Gansu 730030, China
出版时间: 2024-09-28 doi: 10.11855/j.issn.0577-7402.1579.2024.0418
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摘要
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白细胞介素-1受体相关激酶4(IRAK4)在TLRs/IL-1R信号通路中发挥着关键的信号转导及调控作用，协调涉及免疫系统启动、细胞因子产生和细胞增殖与分化的多种炎症途径，与血液系统恶性肿瘤的发病机制和进展有关，包括骨髓增生异常综合征、急性髓系白血病、慢性淋巴细胞白血病和淋巴瘤等疾病。因此，IRAK4可能为血液系统恶性肿瘤的有效治疗靶点。本文就IRAK4的结构和功能及其在血液系统恶性肿瘤中的作用机制和治疗等方面的研究进展进行综述，旨在为揭示相关疾病的发生机制和靶向治疗研究提供参考。

白细胞介素-1受体相关激酶4  /  血液系统恶性肿瘤  /  发病机制  /  靶向治疗

Interleukin-1 receptor associated kinase 4 (IRAK4) plays a crucial role in signal transduction and regulation in the TLRs/IL-1R signaling pathway, coordinating multiple inflammatory pathways involving immune system activation, cytokine production, and cell proliferation and differentiation. IRAK4 is associated with the pathogenesis and progression of hematological malignancies, including myelodysplastic syndrome, acute myeloid leukemia, chronic lymphocytic leukemia, and lymphoma. Therefore, IRAK4 may serve as an effective therapeutic target for hematologic malignancies. This review summarizes the research advances in the structure and function of IRAK4, as well as its mechanism of action and therapeutic implications in hematological malignancies, aiming to provide insights into pathogenesis of related diseases and targeted therapy research.

Interleukin-1 receptor associated kinase 4  /  hematological malignancies  /  pathogenesis  /  targeted therapy
商颖, 李莉娟, 张连生. IRAK4在血液系统恶性肿瘤中的作用及其机制研究进展. 解放军医学杂志, 2024 , 49 (9) : 1094 -1098 . DOI: 10.11855/j.issn.0577-7402.1579.2024.0418
Ying Shang, Li-Juan Li, Lian-Sheng Zhang. Research progress on the role and mechanism of IRAK4 in hematological malignancies[J]. Medical Journal of Chinese People’s Liberation Army, 2024 , 49 (9) : 1094 -1098 . DOI: 10.11855/j.issn.0577-7402.1579.2024.0418
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血液系统恶性肿瘤起源于造血系统，是由于造血干细胞或祖细胞发生恶变，进而阻滞在不同分化阶段，不能进一步成熟而发生的疾病。血液系统恶性肿瘤发病率逐年上升，对公众健康构成严重威胁。白细胞介素-1受体相关激酶4(interleukin-1 receptor associated kinase 4，IRAK4)是丝氨酸-苏氨酸激酶IRAK家族的成员之一，在Toll样受体(Toll like receptor，TLR)天然免疫反应的信号转导中起着承上启下的重要作用[1]。有研究显示，IRAK4与骨髓增生异常综合征(myelodysplastic syndromes，MDS)、白血病、淋巴瘤等血液系统恶性肿瘤的发生发展相关，并影响疾病的预后，有望成为新的治疗靶点。
IRAK4在介导TLR/白细胞介素(interleukin，IL)-1受体结合启动的信号中扮演重要角色，可通过启动免疫应答、产生细胞因子、影响细胞周期来介导细胞的增殖、分化及凋亡，从而参与血液系统恶性肿瘤的发生和发展。本文综述近年来IRAK4在血液系统恶性肿瘤中的主要研究进展，以期进一步揭示相关疾病的发生机制，为疾病预后的评估和靶向治疗提供理论参考。
1 IRAK4的结构和功能及其在血液系统恶性肿瘤中的表达
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1.1 分子结构和功能
IRAK4是一种蛋白激酶，包含一个N端死亡结构域(death domain，DD)、一个ProST结构域和一个激酶结构域(kinase domain，KD)。DD可介导蛋白与髓样分化因子88(myeloid differentiation factor 88，MYD88)或其他信号分子的相互作用，并激活下游信号通路，这对信号转导是必不可少的；ProST 区富含多个磷酸化位点，而KD对蛋白的表达和激酶活性的调节很重要[2-4]。其中，IRAK4独特的酪氨酸门卫(gatekeeper)创造了一个不寻常的腺嘌呤核苷三磷酸(ATP)结合位点，这对激酶/小分子选择性至关重要，因此，可通过这一独特的分子特征来设计高选择性的IRAK激酶抑制剂[5]。IRAK4是炎症反应通路中的关键蛋白，可参与TLR信号通路的传递；其向TLR/IL-1R结构域的招募是由信号转接器MYD88介导的[6]，它们共同形成Myddosome复合物，促进IRAK4的自磷酸化和激活[7]。在受体复合物上IRAK4招募并激活IRAK1，IRAK1迅速磷酸化并离开受体复合物，与适配器和肿瘤坏死因子受体相关因子6(tumor necrosis factor receptor-associated factor 6，TRAF6)相互作用[8]，介导核因子κB(nuclear factor kappa B，NF-κB)和丝裂原活化蛋白激酶(mitogen-activated protein kinase，MAPK)通路的激活[9]，促进炎性因子分泌、细胞增殖和分化等。
IRAK4是Myddosome活性的主要调节因子，控制Myddosome的稳定性和信号转导终止，在先天免疫反应中发挥重要作用；其作用可分为激酶活性和支架作用。IRAK4的激酶活性对于MYD88依赖的炎性因子的产生是必不可少的，而其支架作用在Myddosome组装和促进NF-κB和MAPK信号转导中也是不可或缺的[10]。靶向IRAK4抑制激酶活性，但靶标仍然有效，从而降低了抑制剂的潜力。为达到预期的疗效，针对IRAK4激酶活性的抑制剂和支架的降解剂正在研制中[11]。因此，未来有必要进一步探究IRAK4激酶活性和支架作用分别在疾病发生过程中扮演的角色。
1.2 在血液系统恶性肿瘤中的表达
在MDS和急性髓系白血病(acute myeloid leukemia，AML)中，剪接因子 3B亚基1(splicing factor 3B subunit 1，SF3B1)突变和U2辅助因子1(U2 auxiliary factor 1，U2AF1)突变可分别导致外显子6和4的保留，从而编码IRAK4活性亚型IRAK4-L。IRAK4-L是MDS和AML中主要的选择性剪接异构体，是一个更长、稳定、功能活跃的亚型，其包含整个死亡结构域和激酶结构域，可与MYD88相作用，导致NF-κB的大量激活。相比之下，健康的造血细胞主要表达IRAK4-S，并减弱与MYD88的结合，降低NF-κB激活电位[12-13]。MYD88突变引起的Myddosome信号异常激活是一个已知的淋巴瘤发生的驱动因素，在38%~71%的原发性中枢神经系统淋巴瘤(primary central nervous system lymphoma，PCNSL)、39%的活化B细胞样弥漫大B细胞淋巴瘤(activated B-cell-like diffuse large B-cell lymphoma，ABC DLBCL)、87%的淋巴浆细胞性淋巴瘤(lymphoplasmacytic lymphoma，LPL)、86%~100%的华氏巨球蛋白血症(Waldenstrm's macroglobulinemia，WM)和少数边缘区淋巴瘤(marginal zone lymphoma，MZL)中可见该突变[14]；而MYD88下游的IRAK4和NF-κB在PCNSL中高表达[15]。IRAK4在血液系统恶性肿瘤中表达上调导致NF-κB活性增强，促进疾病的发生，突出了IRAK4作为治疗靶点的可能性。此外，IRAK4基因敲除小鼠和MYD88敲除小鼠表型相似，均缺乏对脂多糖的反应能力，细胞因子产生严重受损[16-17]；而IRAK4和MYD88缺陷的患者免疫功能受损，也呈现相似的临床表现[18]。目前直接针对MYD88的努力在很大程度上是不成功的[19]，所以靶点药物的研究主要集中在针对IRAK4[14,20-21]上。
2 IRAK4与血液系统恶性肿瘤细胞的增殖和分化
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2.1 IRAK4与血液系统恶性肿瘤细胞的增殖
研究显示，IRAK4的表达和激酶活性是血液系统恶性肿瘤细胞功能所必需的，且可促进该类细胞的增殖。Guidetti等[22]在MZL模型中，采用流式细胞仪检测IRAK4激酶抑制是否影响细胞周期分布，发现IRAK4激酶抑制剂CA-4948处理细胞可诱导亚G0期细胞的中度增加，降低增殖细胞的百分比，提示IRAK4可影响恶性肿瘤细胞周期，促进其增殖。Ngo等[23]发现，IRAK4下调对具有MYD88 L265P突变的ABC DLBCL系具有毒性，而对生发中心B细胞样(germinal center B-cell-like，GCB)DLBCL系和骨髓瘤系没有毒性；野生型IRAK4在IRAK4 shRNA诱导后可挽救ABC DLBCL细胞株，但激酶失活的IRAK4亚型却不能；同时，IRAK4激酶抑制剂可杀死ABC DLBCL株，但不能杀死GCB DLBCL和骨髓瘤株。上述结果均提示ABC DLBCL依赖于IRAK4激酶活性来转导MYD88 L265P信号，从而促进细胞生存。Smith等[13]发现，在异种移植小鼠实验中，敲低IRAK4-L可削弱白血病祖细胞功能，减少细胞集落形成；IRAK4-L表达降低不损害正常CD34+细胞的祖细胞功能，但会导致髓系和红系祖细胞集落中度增加，提示恶性肿瘤细胞增殖对IRAK4-L有特异性需求；采用CA-4948抑制MDS/AML细胞株的IRAK4激酶活性可导致体外白血病细胞功能下降；在异种移植小鼠，IRAK4抑制剂治疗后骨髓、脾和肝中的白血病细胞较对照组浸润减少；U2AF1突变MDS患者的异种移植瘤，在CA-4948处理后MDS细胞的移植减少了50%。以上结果显示，IRAK4对血液系统恶性肿瘤细胞增殖是必需的，且抑制IRAK4可抑制恶性肿瘤细胞的生长。
2.2 IRAK4与血液系统恶性肿瘤细胞的分化
IRAK4可能影响血液系统恶性肿瘤细胞的分化过程，导致细胞恶性程度增加。在SF3B1突变细胞中，IRAK4-L的表达诱导TRAF6激活，导致细胞周期依赖蛋白激酶2(cyclin-dependent kinase 2，CDK2)的赖氨酸63(Lysine63，K63)残基泛素化，与造血分化的阻断有关。体外使用CDK2抑制剂治疗可导致造血集落形成增多和骨髓分化增加。用CA-4948抑制IRAK4或敲除IRAK4，可减少NF-κB激活和炎性因子的产生，并增强体外骨髓分化和减少异种移植模型中的肿瘤细胞生长。用IRAK4抑制剂处理健康的人造血干/祖细胞并无导致任何明显的集落数量变化[12]。在另一项体外实验中，IRAK4-L的缺失导致单核细胞分化标记物CD14表达增加，造血干/祖细胞标记物CD34表达减少，提示IRAK4-L是维持白血病细胞原始造血状态所必需的。在克隆检测中，siRNA介导的IRAK4基因敲除或药物抑制后，培养来自于U2AF1突变MDS和AML患者的原始患者源性细胞，IRAK4敲除和CA-4948抑制均可导致红细胞和骨髓分化增强；相比之下，经CA-4948处理后正常的CD34+细胞分化没有改变[13]。以上结果提示，IRAK4是缓解细胞分化阻滞的靶点。
3 IRAK4在血液系统恶性肿瘤中的预后评估价值
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研究显示，IRAK4在MDS中的过表达与较差的预后特征相关[12]。IRAK4-L表达水平较高的队列血小板计数、红细胞较低而白血病细胞计数较多，所有这些都是预后较差的临床特征；在具有复杂细胞遗传学的不良风险AML患者中IRAK4-L升高尤为明显；而IRAK4抑制可导致二次移植中MDS克隆细胞减少，抑制MDS的进展。在另一项研究中，对临床预后差的一组可调控RNA亚型转换的基因进行多变量Cox回归分析，结果显示，这些基因的单个外显子包含/排除事件与AML患者总生存期明显相关；功能富集分析显示，与AML较差预后相关的不同外显子使用的基因在RNA剪接通路、先天免疫和NF-κB信号通路中富集；在这些基因中，IRAK4亚型切换的幅度在AML样本中非常明显，而且仅包含外显子4与较差的预后相关；在AML患者中观察到，与IRAK4-L水平较低的患者相比，IRAK4-L水平升高的患者预后较差[13]。Delvecchio等[24]对GEO数据库中检索到的慢性淋巴细胞白血病(chronic lymphocytic leukemia，CLL)患者mRNA表达数据的统计分析结果显示，与IRAK4低表达组相比，IRAK4高表达组患者的总生存期较短。以上研究提示，IRAK4的表达水平可能预测血液系统恶性肿瘤的预后，为个体化治疗提供依据。
4 IRAK4抑制剂在血液系统恶性肿瘤中的治疗作用及其安全性评估
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4.1 IRAK4抑制剂的治疗作用
抑制IRAK4的活性或表达可能成为治疗血液系统恶性肿瘤的新靶点。已有研究显示，抑制IRAK4可抑制血液系统恶性肿瘤细胞的增殖并诱导细胞凋亡[24]。CA-4948是一种小分子强效IRAK4和FMS样酪氨酸激酶3(FMS-like tyrosine kinase 3，FLT3)抑制剂，在临床前研究中显示有治疗血液系统恶性肿瘤的作用[25]。ABC DLCBL肿瘤异种移植模型的研究显示，CA-4948表现出抗肿瘤活性，且与伊布替尼联合治疗时表现出协同的肿瘤生长抑制作用[25]。在有效暴露下，CA-4948在动物的毒性研究中均具有良好的耐受性；展现了IRAK4激酶抑制剂作为单药或联合其他药物治疗DLBCL的潜力。一项采用MZL肿瘤模型的临床前研究显示，MYD88 L265P突变的存在使CA-4948作为单剂具有敏感性；CA-4948联合布鲁顿酪氨酸蛋白激酶(Bruton's tyrosine kinase，BTK)和磷脂酰肌醇激酶(phosphoinositide 3-kinase，PI3K)抑制剂也具有强烈的协同作用，诱导凋亡淋巴瘤细胞数量明显增加，有利于PI3K和BTK抑制剂的抗肿瘤活性，并可克服MZL模型的获得性耐药。在BTK抑制剂耐药模型中，CA-4948和BTK抑制剂单独用药都不能诱导抗增殖反应，提示两种化合物的联合应用是有效的。IRAK4抑制剂CA-4948在淋巴瘤患者中显示出了早期安全性和临床活性[22]。CA-4948也可透过血脑屏障，对PCNSL具有单药活性。单药口服CA-4948可抑制颅内肿瘤中IRAK4下游的信号通路，降低MAPK和NF-κB活性蛋白的表达，具有抗肿瘤活性，可改善PCNSL模型的生存。研究还显示，在PCNSL临床前模型中，有很大一部分活性NF‑κB表达来自肿瘤免疫微环境(tumor microenvironment，TME)，包括肿瘤反应性星形胶质细胞和免疫细胞。脑肿瘤TME激活Myddosome信号，作为一种对源自癌性病变的持续炎症信号的强制性反应，可能增强支持肿瘤扩张的病理环境。MYD88/IRAK4在PCNSL中上调，并在这些脑恶性肿瘤的独特TME中具有深远的相互作用。基于肿瘤和TME中与细胞内信号通路相互作用的机制，CA-4948存在与其他药物协同作用的潜力[15]。CA-4948目前正在临床试验中进行评估，用于复发或难治性血液恶性肿瘤患者，包括非霍奇金淋巴瘤、MDS和AML[26]。在高危MDS和复发难治AML的临床试验中，选定样本的RNA-seq显示IRAK4-L的相对表达量随着CA-4948的反应而下降，初步结果显示其具有良好的耐受性和有效性，特别是U2AF1/SF3B1/FLT3突变患者[26]。患者接受CA-4948单药或联合阿扎胞苷或venetoclax治疗，7例剪接体突变的高危MDS患者的中期试验结果显示，57%的患者达到骨髓完全缓解(complete response，CR)；而在没有剪接体突变的患者中，CR是罕见的；在2/3经治疗的FLT3 AML患者中，FLT3突变的克隆体未检测到[27-28]。
IRAK4抑制剂可能通过引起抗凋亡和促增殖基因上调，从而导致药物疗效的降低。在ABC DLBCL中的研究显示，IRAK4在肿瘤细胞存活中发挥了作用，尽管IRAK4激酶抑制和蛋白降解均可抑制TLR激动剂诱导的NF-κB和MAPK的激活及细胞因子的产生，但均不会导致ABC DLBCL细胞系死亡或生长抑制；但当NF-κB通路被IRAK4激酶抑制剂抑制时，几个促增殖基因(包括BRAF、CDK6、PI3K通路的PIK3R1和RICTOR)和抗凋亡基因(BCL-2和BIRC6)均明显上调，提示抗凋亡和促增殖通路可能被激活，有助于维持DLBCL细胞的生存和增殖[14]。这一结果仍需在体内系统和其他血液系统恶性肿瘤中进行验证，并进一步完善相关研究以揭示其具体机制。此外，有研究报道，一个由MYD88 L265P、TLR9和B细胞受体组成的多蛋白超复合物与mTOR共同定位于内溶酶体，驱动NF-κB和mTOR信号通路，支持淋巴瘤细胞存活，并可鉴别对伊布替尼抑制NF-κB治疗有反应的患者[29]。以上研究提供了对IRAK4激酶抑制剂的联合用药在血液系统恶性肿瘤疗效机制深入探究的理论依据。
此外，还有研究显示，IRAK-1/4抑制剂R191可影响NF-κB和Akt信号转导，增强硼替佐米、ibtrutinib等化疗药物的疗效，克服华氏巨球蛋白血症的耐药性[30]。IRAK4抑制剂ND2158可抑制髓系细胞和T细胞的活性，降低NF-κB和STAT信号转导、细胞因子的分泌、增殖和迁移，延缓肿瘤进展[31]。IRAK4和免疫调节药物(immunodulatory drugs，IMiDs)底物(Ikaros/Aiolos)的双重降解剂KT-413在MYD88突变的DLBCL模型中显示出很强的抗肿瘤活性。KT-413与利妥昔单抗或BTK抑制剂联合治疗在异种移植体内也显示出强烈的加性活性[32]。基于这些结果，IRAK4抑制剂或降解剂具有作为单一药物或与其他药物联合治疗血液系统恶性肿瘤的潜力。
4.2 安全性评估
IRAK4缺乏症是先天免疫系统的原发性免疫缺陷。患有这种疾病的儿童易发生危及生命的细菌感染。尽管存在严重感染，但IRAK4 缺乏导致的炎症全身性特征减少或消失[33]。有研究报道，IRAK4缺陷患者的主要感染表型是化脓性细菌感染，主要由肺炎链球菌、金黄色葡萄球菌或铜绿假单胞菌引起；还存在非侵入性化脓性细菌感染，主要影响皮肤和上呼吸道，其中坏死性感染尤为常见。IRAK4缺陷患者在童年时期感染的概率较高，在进入青少年时期后，这种风险逐渐降低[34]；但仍有IRAK4缺乏症成年患者出现致命性脑膜炎的病例[35]。先天免疫系统的缺陷导致患者无法快速识别病原体并激活免疫反应，从而导致对严重或复发性感染的易感性。抑制IRAK4激酶活性或降解IRAK4，可实现对相关信号通路的部分或完全抑制。所以，抑制IRAK4的治疗方法可能带来一定的不良反应，如免疫抑制、感染等。因此，在临床应用前，需对其安全性进行充分评估。值得注意的是，目前临床前试验和临床试验中应用的IRAK4抑制剂的耐受性均良好。
5 总结与展望
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近年研究表明，IRAK4在血液系统恶性肿瘤的发生发展中发挥重要作用。越来越多的研究显示，IRAK4抑制剂可减少炎性因子的产生，促进肿瘤细胞分化和减少肿瘤细胞克隆，并能克服耐药，与其他靶向药物联合应用时可协同作用获得更好的疗效；已有临床试验验证了部分IRAK4抑制剂的可耐受性和有效性。然而，目前关于IRAK4的研究仍存在诸多不足，IRAK4在不同血液系统恶性肿瘤发生和进展中的调控机制仍需进一步探讨，IRAK4抑制剂引起的抗凋亡和促增殖基因上调、T细胞活性抑制等问题也亟待深入研究，临床试验样本量仍需扩大，以期为血液系统恶性肿瘤的发病机制、预后评估及治疗研究提供更充分的理论依据。
基金
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  • 国家自然科学基金(82360029)
文献
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参考文献 引证文献
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2024年第49卷第9期
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doi: 10.11855/j.issn.0577-7402.1579.2024.0418
  • 接收时间：2023-11-29
  • 首发时间：2025-11-21
  • 出版时间：2024-09-28
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  • 收稿日期：2023-11-29
  • 录用日期：2024-03-22
基金
National Natural Science Foundation of China(82360029)
国家自然科学基金(82360029)
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    兰州大学第二医院血液科，甘肃兰州 730030

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张连生，E-mail：
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
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