• 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

Fms 样酪氨酸激酶 3 内部串联重复通过表观遗传激活急性髓系白血病细胞中的检查点激酶 1。

Fms-like tyrosine kinase 3-internal tandem duplications epigenetically activates checkpoint kinase 1 in acute myeloid leukemia cells.

机构信息

Department of Critical Care Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China.

Department of Hematology, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China.

出版信息

Sci Rep. 2021 Jun 24;11(1):13236. doi: 10.1038/s41598-021-92566-5.

DOI:10.1038/s41598-021-92566-5
PMID:34168220
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8225911/
Abstract

It is not clear how Fms-like tyrosine kinase 3-internal tandem duplications (FLT3-ITD) regulates checkpoint kinase 1 (CHK1) in acute myeloid leukemia (AML). In this study, we investigated the regulatory effect of FLT3-ITD on CHK1. Our results showed that CHK1 was highly expressed in FLT3-ITD positive AML. The overall survival rate and disease-free survival rate of AML patients with high CHK1 level were lower than those of patients with low CHK1 level. Mechanistically, FLT3-ITD recruited p300 to the CHK1 promoter and subsequently acetylated H3K27, thereby enhancing the transcription of CHK1. Interfering with the expression of CHK1 significantly inhibited the cell proliferation and induced cell apoptosis in FLT3-ITD positive MV4-11 cells. In addition, CHK1 knockdown promoted the sensitivity of MV4-11 cells to the epigenetic inhibitors JQ1 and C646. This study discovers a new therapeutic target for FLT3-ITD + AML and provided evidence for the combination of epigenetic inhibitors for AML treatment.

摘要

FLT3-ITD 如何调节急性髓系白血病（AML）中的细胞检查点激酶 1（CHK1）尚不清楚。在这项研究中，我们研究了 FLT3-ITD 对 CHK1 的调节作用。结果表明，CHK1 在 FLT3-ITD 阳性 AML 中高度表达。CHK1 水平高的 AML 患者的总生存率和无病生存率均低于 CHK1 水平低的患者。在机制上，FLT3-ITD 将 p300 募集到 CHK1 启动子上，随后乙酰化 H3K27，从而增强 CHK1 的转录。干扰 CHK1 的表达显著抑制了 FLT3-ITD 阳性 MV4-11 细胞的增殖，并诱导其细胞凋亡。此外，CHK1 敲低促进了 MV4-11 细胞对表观遗传抑制剂 JQ1 和 C646 的敏感性。这项研究发现了 FLT3-ITD+AML 的一个新的治疗靶点，并为 AML 的表观遗传抑制剂联合治疗提供了证据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e83/8225911/2d02d56b4722/41598_2021_92566_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e83/8225911/6f199146a1fb/41598_2021_92566_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e83/8225911/b7665ff274d4/41598_2021_92566_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e83/8225911/d762b9a3769c/41598_2021_92566_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e83/8225911/7499a6d35de0/41598_2021_92566_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e83/8225911/2d02d56b4722/41598_2021_92566_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e83/8225911/6f199146a1fb/41598_2021_92566_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e83/8225911/b7665ff274d4/41598_2021_92566_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e83/8225911/d762b9a3769c/41598_2021_92566_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e83/8225911/7499a6d35de0/41598_2021_92566_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e83/8225911/2d02d56b4722/41598_2021_92566_Fig5_HTML.jpg

相似文献

1
Fms-like tyrosine kinase 3-internal tandem duplications epigenetically activates checkpoint kinase 1 in acute myeloid leukemia cells.Fms 样酪氨酸激酶 3 内部串联重复通过表观遗传激活急性髓系白血病细胞中的检查点激酶 1。
Sci Rep. 2021 Jun 24;11(1):13236. doi: 10.1038/s41598-021-92566-5.
2
All-trans retinoic acid exerts selective anti-FLT3-ITD acute myeloid leukemia efficacy through downregulating Chk1 kinase.全反式维甲酸通过下调 Chk1 激酶选择性发挥抗 FLT3-ITD 急性髓系白血病作用。
Cancer Lett. 2020 Mar 31;473:130-138. doi: 10.1016/j.canlet.2019.12.045. Epub 2020 Jan 2.
3
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.
4
Prevalence of FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD+) in de novo acute myeloid leukemia patients categorized according to cytogenetic risk.根据细胞遗传学风险分类的初发急性髓系白血病患者中FMS样酪氨酸激酶3/内部串联重复（FLT3/ITD+）的患病率。
Sao Paulo Med J. 2009 Jan;127(1):23-7. doi: 10.1590/s1516-31802009000100006.
5
The protein tyrosine phosphatase, Shp2, positively contributes to FLT3-ITD-induced hematopoietic progenitor hyperproliferation and malignant disease in vivo.蛋白酪氨酸磷酸酶 Shp2 正向促进 FLT3-ITD 诱导的体内造血祖细胞过度增殖和恶性疾病。
Leukemia. 2013 Feb;27(2):398-408. doi: 10.1038/leu.2012.308. Epub 2012 Oct 22.
6
[Correlation of Fms-like tyrosine kinase 3 (FLT3) gene expression to FLT3/internal tandem duplication mutation in peripheral blood of acute myeloid leukemia.].急性髓系白血病患者外周血中Fms样酪氨酸激酶3（FLT3）基因表达与FLT3内部串联重复突变的相关性
Ai Zheng. 2009 Jun;28(6):632-6.
7
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.
8
FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation.FLT3-ITD 通过 FLT3-ITD 特异性 STAT5 激活上调 MCL-1 促进急性髓系白血病干细胞存活。
Blood. 2009 Dec 3;114(24):5034-43. doi: 10.1182/blood-2008-12-196055. Epub 2009 Oct 6.
9
Integrin alphavbeta3 enhances β-catenin signaling in acute myeloid leukemia harboring Fms-like tyrosine kinase-3 internal tandem duplication mutations: implications for microenvironment influence on sorafenib sensitivity.整合素αvβ3增强携带Fms样酪氨酸激酶3内部串联重复突变的急性髓系白血病中的β-连环蛋白信号传导：对微环境对索拉非尼敏感性影响的启示
Oncotarget. 2016 Jun 28;7(26):40387-40397. doi: 10.18632/oncotarget.9617.
10
Association of the EGF-TM7 receptor CD97 expression with FLT3-ITD in acute myeloid leukemia.急性髓系白血病中表皮生长因子-TM7受体CD97表达与FLT3-ITD的相关性
Oncotarget. 2015 Nov 17;6(36):38804-15. doi: 10.18632/oncotarget.5661.

引用本文的文献

1
Recommended Tool Compounds: Thienotriazolodiazepines-Derivatized Chemical Probes to Target BET Bromodomains.推荐的工具化合物：靶向BET溴结构域的噻吩并三唑二氮杂卓衍生化学探针。
ACS Pharmacol Transl Sci. 2025 Mar 14;8(4):978-1012. doi: 10.1021/acsptsci.4c00726. eCollection 2025 Apr 11.
2
Concurrent inhibition of p300/CBP and FLT3 enhances cytotoxicity and overcomes resistance in acute myeloid leukemia.同时抑制p300/CBP和FLT3可增强急性髓系白血病的细胞毒性并克服耐药性。
Acta Pharmacol Sin. 2025 May;46(5):1390-1403. doi: 10.1038/s41401-025-01479-w. Epub 2025 Jan 30.
3
Dual inhibition of CHK1/FLT3 enhances cytotoxicity and overcomes adaptive and acquired resistance in FLT3-ITD acute myeloid leukemia.

本文引用的文献

1
All-trans retinoic acid exerts selective anti-FLT3-ITD acute myeloid leukemia efficacy through downregulating Chk1 kinase.全反式维甲酸通过下调 Chk1 激酶选择性发挥抗 FLT3-ITD 急性髓系白血病作用。
Cancer Lett. 2020 Mar 31;473:130-138. doi: 10.1016/j.canlet.2019.12.045. Epub 2020 Jan 2.
2
Investigational CHK1 inhibitors in early phase clinical trials for the treatment of cancer.在早期临床试验中用于癌症治疗的 CHK1 抑制剂的研究。
Expert Opin Investig Drugs. 2019 Dec;28(12):1095-1100. doi: 10.1080/13543784.2019.1694661. Epub 2019 Nov 29.
3
Not Only Mutations Matter: Molecular Picture of Acute Myeloid Leukemia Emerging from Transcriptome Studies.
双重抑制 CHK1/FLT3 增强了对 FLT3-ITD 急性髓系白血病的细胞毒性，并克服了适应性和获得性耐药性。
Leukemia. 2023 Mar;37(3):539-549. doi: 10.1038/s41375-022-01795-8. Epub 2022 Dec 16.
并非只有突变起作用：转录组研究揭示的急性髓系白血病分子图景
J Oncol. 2019 Jul 30;2019:7239206. doi: 10.1155/2019/7239206. eCollection 2019.
4
The FLT3-ITD mutation and the expression of its downstream signaling intermediates STAT5 and Pim-1 are positively correlated with CXCR4 expression in patients with acute myeloid leukemia.FLT3-ITD 突变及其下游信号转导介质 STAT5 和 Pim-1 的表达与急性髓系白血病患者的 CXCR4 表达呈正相关。
Sci Rep. 2019 Aug 21;9(1):12209. doi: 10.1038/s41598-019-48687-z.
5
Clinical considerations for the use of FLT3 inhibitors in acute myeloid leukemia.FLT3 抑制剂在急性髓系白血病中的临床应用考虑。
Crit Rev Oncol Hematol. 2019 Sep;141:125-138. doi: 10.1016/j.critrevonc.2019.06.011. Epub 2019 Jun 28.
6
FLT3-ITD cooperates with Rac1 to modulate the sensitivity of leukemic cells to chemotherapeutic agents via regulation of DNA repair pathways.FLT3-ITD 通过调节 DNA 修复途径与 Rac1 合作调节白血病细胞对化疗药物的敏感性。
Haematologica. 2019 Dec;104(12):2418-2428. doi: 10.3324/haematol.2018.208843. Epub 2019 Apr 11.
7
Targeting FLT3 mutations in AML: review of current knowledge and evidence.AML 中 FLT3 突变的靶向治疗：现有知识和证据的综述。
Leukemia. 2019 Feb;33(2):299-312. doi: 10.1038/s41375-018-0357-9. Epub 2019 Jan 16.
8
FLT3 inhibitors in acute myeloid leukemia.FLT3 抑制剂在急性髓系白血病中的应用。
J Hematol Oncol. 2018 Dec 4;11(1):133. doi: 10.1186/s13045-018-0675-4.
9
State-of-the-art strategies for targeting the DNA damage response in cancer.针对癌症中 DNA 损伤反应的最新策略。
Nat Rev Clin Oncol. 2019 Feb;16(2):81-104. doi: 10.1038/s41571-018-0114-z.
10
Bromodomain Drug Discovery - the Past, the Present, and the Future.溴结构域药物发现——过去、现在和未来。
Chem Rec. 2018 Dec;18(12):1808-1817. doi: 10.1002/tcr.201800074. Epub 2018 Oct 5.