• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

酪氨酸激酶抑制可增加 FLT3-ITD 的细胞表面定位，并增强急性髓系白血病的 FLT3 导向免疫治疗。

Tyrosine kinase inhibition increases the cell surface localization of FLT3-ITD and enhances FLT3-directed immunotherapy of acute myeloid leukemia.

机构信息

Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.

German Cancer Consortium (DKTK), partner site Munich, Munich, Germany.

出版信息

Leukemia. 2018 Feb;32(2):313-322. doi: 10.1038/leu.2017.257. Epub 2017 Aug 14.

DOI:10.1038/leu.2017.257
PMID:28895560
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5808080/
Abstract

The fms-related tyrosine kinase 3 (FLT3) receptor has been extensively studied over the past two decades with regard to oncogenic alterations that do not only serve as prognostic markers but also as therapeutic targets in acute myeloid leukemia (AML). Internal tandem duplications (ITDs) became of special interest in this setting as they are associated with unfavorable prognosis. Because of sequence-dependent protein conformational changes FLT3-ITD tends to autophosphorylate and displays a constitutive intracellular localization. Here, we analyzed the effect of tyrosine kinase inhibitors (TKIs) on the localization of the FLT3 receptor and its mutants. TKI treatment increased the surface expression through upregulation of FLT3 and glycosylation of FLT3-ITD and FLT3-D835Y mutants. In T cell-mediated cytotoxicity (TCMC) assays, using a bispecific FLT3 × CD3 antibody construct, the combination with TKI treatment increased TCMC in the FLT3-ITD-positive AML cell lines MOLM-13 and MV4-11, patient-derived xenograft cells and primary patient samples. Our findings provide the basis for rational combination of TKI and FLT3-directed immunotherapy with potential benefit for FLT3-ITD-positive AML patients.

摘要

在过去的二十年中，人们对 fms 相关酪氨酸激酶 3（FLT3）受体进行了广泛的研究，涉及到致癌改变，这些改变不仅可以作为预后标志物，还可以作为急性髓系白血病（AML）的治疗靶点。在这种情况下，内部串联重复（ITD）引起了特别的关注，因为它们与不良预后相关。由于序列依赖性蛋白质构象变化，FLT3-ITD 倾向于自身磷酸化，并表现出组成型细胞内定位。在这里，我们分析了酪氨酸激酶抑制剂（TKI）对 FLT3 受体及其突变体定位的影响。TKI 治疗通过上调 FLT3 和 FLT3-ITD 和 FLT3-D835Y 突变体的糖基化，增加了表面表达。在 T 细胞介导的细胞毒性（TCMC）测定中，使用双特异性 FLT3×CD3 抗体构建体，与 TKI 治疗联合使用增加了 FLT3-ITD 阳性 AML 细胞系 MOLM-13 和 MV4-11、患者来源的异种移植物细胞和原发性患者样本中的 TCMC。我们的发现为 TKI 和 FLT3 导向免疫疗法的合理联合提供了基础，可能对 FLT3-ITD 阳性 AML 患者有益。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa90/5808080/5ff34db7d3b1/leu2017257f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa90/5808080/55745280d57f/leu2017257f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa90/5808080/dbb76a8e6fbf/leu2017257f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa90/5808080/3db1ab20a113/leu2017257f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa90/5808080/6cb8e8288cf9/leu2017257f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa90/5808080/9528160b90cb/leu2017257f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa90/5808080/9721e5d511a3/leu2017257f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa90/5808080/5ff34db7d3b1/leu2017257f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa90/5808080/55745280d57f/leu2017257f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa90/5808080/dbb76a8e6fbf/leu2017257f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa90/5808080/3db1ab20a113/leu2017257f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa90/5808080/6cb8e8288cf9/leu2017257f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa90/5808080/9528160b90cb/leu2017257f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa90/5808080/9721e5d511a3/leu2017257f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa90/5808080/5ff34db7d3b1/leu2017257f7.jpg

相似文献

1
Tyrosine kinase inhibition increases the cell surface localization of FLT3-ITD and enhances FLT3-directed immunotherapy of acute myeloid leukemia.酪氨酸激酶抑制可增加 FLT3-ITD 的细胞表面定位，并增强急性髓系白血病的 FLT3 导向免疫治疗。
Leukemia. 2018 Feb;32(2):313-322. doi: 10.1038/leu.2017.257. Epub 2017 Aug 14.
2
FLT3 inhibition upregulates HDAC8 via FOXO to inactivate p53 and promote maintenance of FLT3-ITD+ acute myeloid leukemia.FLT3 抑制通过 FOXO 上调 HDAC8，使 p53 失活，从而促进 FLT3-ITD+ 急性髓系白血病的维持。
Blood. 2020 Apr 23;135(17):1472-1483. doi: 10.1182/blood.2019003538.
3
Internal tandem duplication mutations in the tyrosine kinase domain of FLT3 display a higher oncogenic potential than the activation loop D835Y mutation.FLT3酪氨酸激酶结构域中的内部串联重复突变比激活环D835Y突变显示出更高的致癌潜能。
Ann Hematol. 2018 May;97(5):773-780. doi: 10.1007/s00277-018-3245-5. Epub 2018 Jan 25.
4
Dual inhibition of Fes and Flt3 tyrosine kinases potently inhibits Flt3-ITD+ AML cell growth.对Fes和Flt3酪氨酸激酶的双重抑制可有效抑制Flt3-ITD+急性髓系白血病细胞的生长。
PLoS One. 2017 Jul 20;12(7):e0181178. doi: 10.1371/journal.pone.0181178. eCollection 2017.
5
PRMT1-mediated FLT3 arginine methylation promotes maintenance of FLT3-ITD acute myeloid leukemia.PRMT1 介导的 FLT3 精氨酸甲基化促进 FLT3-ITD 急性髓系白血病的维持。
Blood. 2019 Aug 8;134(6):548-560. doi: 10.1182/blood.2019001282. Epub 2019 Jun 19.
6
Modulation of FLT3-ITD Localization and Targeting of Distinct Downstream Signaling Pathways as Potential Strategies to Overcome FLT3-Inhibitor Resistance.调控 FLT3-ITD 定位和靶向不同下游信号通路作为克服 FLT3 抑制剂耐药性的潜在策略。
Cells. 2021 Nov 3;10(11):2992. doi: 10.3390/cells10112992.
7
Combined inhibition of Notch and FLT3 produces synergistic cytotoxic effects in FLT3/ITD acute myeloid leukemia.联合抑制 Notch 和 FLT3 在 FLT3/ITD 急性髓系白血病中产生协同细胞毒性作用。
Signal Transduct Target Ther. 2020 Mar 13;5(1):21. doi: 10.1038/s41392-020-0108-z.
8
NFATc1 as a therapeutic target in FLT3-ITD-positive AML.NFATc1 作为 FLT3-ITD 阳性 AML 的治疗靶点。
Leukemia. 2015 Jul;29(7):1470-7. doi: 10.1038/leu.2015.95. Epub 2015 Apr 14.
9
Over-expression of FoxM1 is associated with adverse prognosis and FLT3-ITD in acute myeloid leukemia.FoxM1 的过表达与急性髓系白血病的不良预后和 FLT3-ITD 相关。
Biochem Biophys Res Commun. 2014 Mar 28;446(1):280-5. doi: 10.1016/j.bbrc.2014.02.094. Epub 2014 Feb 28.
10
Selective FLT3 inhibition of FLT3-ITD+ acute myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns.FLT3-ITD+ 急性髓系白血病的选择性 FLT3 抑制导致继发 D835Y 突变：新兴临床耐药模式的模型。
Leukemia. 2012 Jul;26(7):1462-70. doi: 10.1038/leu.2012.52. Epub 2012 Feb 22.

引用本文的文献

1
Targeting Oncogenic Activity and Signalling of Mutant Receptor Tyrosine Kinase FLT3.靶向致癌活性及突变型受体酪氨酸激酶FLT3的信号传导
Cancers (Basel). 2025 Sep 7;17(17):2931. doi: 10.3390/cancers17172931.
2
Advances in the application of patient-derived xenograft models in acute leukemia resistance.患者来源的异种移植模型在急性白血病耐药性研究中的应用进展
Cancer Drug Resist. 2025 May 28;8:23. doi: 10.20517/cdr.2025.18. eCollection 2025.
3
CD99: A Key Regulator in Immune Response and Tumor Microenvironment.CD99：免疫反应和肿瘤微环境中的关键调节因子。

本文引用的文献

1
Recurrent Mutations in Cyclin D3 Confer Clinical Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia.Cyclin D3 中的反复突变导致急性髓系白血病对 FLT3 抑制剂产生临床耐药性。
Clin Cancer Res. 2021 Jul 15;27(14):4003-4011. doi: 10.1158/1078-0432.CCR-20-3458. Epub 2021 Jun 8.
2
Recent advances and novel agents for FLT3 mutated acute myeloid leukemia.FLT3突变型急性髓系白血病的最新进展与新型药物
Stem Cell Investig. 2014 Mar 20;1:7. doi: 10.3978/j.issn.2306-9759.2014.03.03. eCollection 2014.
3
The new and recurrent FLT3 juxtamembrane deletion mutation shows a dominant negative effect on the wild-type FLT3 receptor.
Biomolecules. 2025 Apr 28;15(5):632. doi: 10.3390/biom15050632.
4
Superior preclinical efficacy of co-treatment with BRG1/BRM and FLT3 inhibitor against AML cells with FLT3 mutations.BRG1/BRM与FLT3抑制剂联合治疗对携带FLT3突变的AML细胞具有卓越的临床前疗效。
Blood Cancer J. 2025 Mar 15;15(1):40. doi: 10.1038/s41408-025-01251-7.
5
Effective eradication of acute myeloid leukemia stem cells with FLT3-directed antibody-drug conjugates.使用FLT3导向抗体-药物偶联物有效根除急性髓性白血病干细胞。
Leukemia. 2025 Mar;39(3):632-642. doi: 10.1038/s41375-024-02510-5. Epub 2025 Jan 27.
6
Immunosuppressive microenvironment in acute myeloid leukemia: overview, therapeutic targets and corresponding strategies.急性髓系白血病中的免疫抑制微环境：概述、治疗靶点及相应策略
Ann Hematol. 2024 Dec;103(12):4883-4899. doi: 10.1007/s00277-024-06117-9. Epub 2024 Nov 28.
7
Accelerating CAR-T Cell Therapies with Small-Molecule Inhibitors.利用小分子抑制剂加速嵌合抗原受体T细胞（CAR-T）疗法
BioDrugs. 2025 Jan;39(1):33-51. doi: 10.1007/s40259-024-00688-9. Epub 2024 Nov 26.
8
and study of FLT3 inhibitors and their application in acute myeloid leukemia.以及 FLT3 抑制剂的研究及其在急性髓系白血病中的应用。
Mol Med Rep. 2024 Dec;30(6). doi: 10.3892/mmr.2024.13353. Epub 2024 Oct 11.
9
Glycosylation: mechanisms, biological functions and clinical implications.糖基化：机制、生物学功能和临床意义。
Signal Transduct Target Ther. 2024 Aug 5;9(1):194. doi: 10.1038/s41392-024-01886-1.
10
Tomatidine, a Steroidal Alkaloid, Synergizes with Cisplatin to Inhibit Cell Viability and Induce Cell Death Selectively on FLT3-ITD+ Acute Myeloid Leukemia Cells.番茄次碱，一种甾体生物碱，与顺铂协同作用，选择性地抑制 FLT3-ITD+ 急性髓系白血病细胞的活力并诱导细胞死亡。
Cell Biochem Biophys. 2024 Sep;82(3):2889-2900. doi: 10.1007/s12013-024-01406-6. Epub 2024 Jul 11.
新的和复发的FLT3近膜区缺失突变对野生型FLT3受体显示出显性负效应。
Sci Rep. 2016 Jun 27;6:28032. doi: 10.1038/srep28032.
4
Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial.索拉非尼联合标准疗法与安慰剂联合标准疗法治疗 60 岁及以下初诊急性髓系白血病患者（SORAML）：一项多中心、2 期、随机对照试验。
Lancet Oncol. 2015 Dec;16(16):1691-9. doi: 10.1016/S1470-2045(15)00362-9. Epub 2015 Nov 6.
5
Impact of FLT3-ITD location on sensitivity to TKI-therapy in vitro and in vivo.FLT3-ITD 位置对体外和体内 TKI 治疗敏感性的影响。
Leukemia. 2016 May;30(5):1220-1225. doi: 10.1038/leu.2015.292. Epub 2015 Oct 21.
6
Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism.阻断 PD-1/PD-L1 轴增强了 CD33/CD3 BiTE 抗体构建体 AMG 330 对 AML 细胞的裂解作用：逆转 T 细胞诱导的免疫逃逸机制。
Leukemia. 2016 Feb;30(2):484-91. doi: 10.1038/leu.2015.214. Epub 2015 Aug 4.
7
Antileukemic Activity of 2-Deoxy-d-Glucose through Inhibition of N-Linked Glycosylation in Acute Myeloid Leukemia with FLT3-ITD or c-KIT Mutations.2-脱氧-D-葡萄糖通过抑制FLT3-ITD或c-KIT突变的急性髓系白血病中的N-连接糖基化发挥抗白血病活性。
Mol Cancer Ther. 2015 Oct;14(10):2364-73. doi: 10.1158/1535-7163.MCT-15-0163. Epub 2015 Jul 23.
8
FLT3 D835 mutations confer differential resistance to type II FLT3 inhibitors.FLT3 D835突变对II型FLT3抑制剂具有不同的耐药性。
Leukemia. 2015 Dec;29(12):2390-2. doi: 10.1038/leu.2015.165. Epub 2015 Jun 25.
9
An advanced preclinical mouse model for acute myeloid leukemia using patients' cells of various genetic subgroups and in vivo bioluminescence imaging.一种使用不同基因亚组患者细胞及体内生物发光成像技术的急性髓系白血病高级临床前小鼠模型。
PLoS One. 2015 Mar 20;10(3):e0120925. doi: 10.1371/journal.pone.0120925. eCollection 2015.
10
Characterization of a bispecific FLT3 X CD3 antibody in an improved, recombinant format for the treatment of leukemia.一种用于治疗白血病的改良重组形式双特异性FLT3 X CD3抗体的特性研究。
Mol Ther. 2015 Apr;23(4):648-55. doi: 10.1038/mt.2015.2. Epub 2015 Jan 12.