• 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

TP53 凋亡网络是 AML 细胞中对 BCL2 抑制产生耐药的主要介质。

The TP53 Apoptotic Network Is a Primary Mediator of Resistance to BCL2 Inhibition in AML Cells.

机构信息

Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon.

Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.

出版信息

Cancer Discov. 2019 Jul;9(7):910-925. doi: 10.1158/2159-8290.CD-19-0125. Epub 2019 May 2.

DOI:10.1158/2159-8290.CD-19-0125
PMID:31048320
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6606338/
Abstract

To study mechanisms underlying resistance to the BCL2 inhibitor venetoclax in acute myeloid leukemia (AML), we used a genome-wide CRISPR/Cas9 screen to identify gene knockouts resulting in drug resistance. We validated , , and as genes whose inactivation results in venetoclax resistance in AML cell lines. Resistance to venetoclax resulted from an inability to execute apoptosis driven by BAX loss, decreased expression of BCL2, and/or reliance on alternative BCL2 family members such as BCL2L1. The resistance was accompanied by changes in mitochondrial homeostasis and cellular metabolism. Evaluation of knockout cells for sensitivities to a panel of small-molecule inhibitors revealed a gain of sensitivity to TRK inhibitors. We relate these observations to patient drug responses and gene expression in the Beat AML dataset. Our results implicate , the apoptotic network, and mitochondrial functionality as drivers of venetoclax response in AML and suggest strategies to overcome resistance. SIGNIFICANCE: AML is challenging to treat due to its heterogeneity, and single-agent therapies have universally failed, prompting a need for innovative drug combinations. We used a genetic approach to identify genes whose inactivation contributes to drug resistance as a means of forming preferred drug combinations to improve AML treatment...

摘要

为了研究急性髓系白血病 (AML) 中对 BCL2 抑制剂 venetoclax 产生耐药性的机制，我们使用全基因组 CRISPR/Cas9 筛选来鉴定导致耐药性的基因敲除。我们验证了 、 和 作为基因失活导致 AML 细胞系对 venetoclax 耐药的基因。对 venetoclax 的耐药性源于无法执行由 BAX 缺失驱动的细胞凋亡，BCL2 表达降低，和/或依赖于 BCL2 家族的替代成员，如 BCL2L1。耐药性伴随着线粒体稳态和细胞代谢的变化。对 基因敲除细胞进行小分子抑制剂敏感性评估显示对 TRK 抑制剂的敏感性增加。我们将这些观察结果与 Beat AML 数据集的患者药物反应和基因表达相关联。我们的结果表明，凋亡网络和线粒体功能作为 AML 中 venetoclax 反应的驱动因素，并提出了克服耐药性的策略。意义：由于 AML 的异质性，其治疗具有挑战性，单一药物治疗普遍失败，因此需要创新的药物组合。我们使用遗传方法来鉴定导致耐药性的基因，作为形成首选药物组合以改善 AML 治疗的一种手段。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930a/6606338/76085993a924/nihms-1528705-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930a/6606338/a3b60eb4e921/nihms-1528705-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930a/6606338/119153074f1c/nihms-1528705-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930a/6606338/7d78a3f1b1bc/nihms-1528705-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930a/6606338/dc328d947aa1/nihms-1528705-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930a/6606338/b9292f50c3f4/nihms-1528705-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930a/6606338/17dae76e9d84/nihms-1528705-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930a/6606338/76085993a924/nihms-1528705-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930a/6606338/a3b60eb4e921/nihms-1528705-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930a/6606338/119153074f1c/nihms-1528705-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930a/6606338/7d78a3f1b1bc/nihms-1528705-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930a/6606338/dc328d947aa1/nihms-1528705-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930a/6606338/b9292f50c3f4/nihms-1528705-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930a/6606338/17dae76e9d84/nihms-1528705-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930a/6606338/76085993a924/nihms-1528705-f0007.jpg

相似文献

1
The TP53 Apoptotic Network Is a Primary Mediator of Resistance to BCL2 Inhibition in AML Cells.TP53 凋亡网络是 AML 细胞中对 BCL2 抑制产生耐药的主要介质。
Cancer Discov. 2019 Jul;9(7):910-925. doi: 10.1158/2159-8290.CD-19-0125. Epub 2019 May 2.
2
Targeting Mitochondrial Structure Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment.靶向线粒体结构可增强急性髓系白血病对 venetoclax 的治疗敏感性。
Cancer Discov. 2019 Jul;9(7):890-909. doi: 10.1158/2159-8290.CD-19-0117. Epub 2019 May 2.
3
A Novel MCL1 Inhibitor Combined with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous Leukemia.一种新型 MCL1 抑制剂与 Venetoclax 联合可挽救 Venetoclax 耐药的急性髓系白血病。
Cancer Discov. 2018 Dec;8(12):1566-1581. doi: 10.1158/2159-8290.CD-18-0140. Epub 2018 Sep 5.
4
Cotargeting BCL-2 and PI3K Induces BAX-Dependent Mitochondrial Apoptosis in AML Cells.联合靶向 BCL-2 和 PI3K 诱导 AML 细胞中 BAX 依赖性线粒体凋亡。
Cancer Res. 2018 Jun 1;78(11):3075-3086. doi: 10.1158/0008-5472.CAN-17-3024. Epub 2018 Mar 20.
5
Inhibition of mitochondrial translation overcomes venetoclax resistance in AML through activation of the integrated stress response.通过激活整合应激反应，抑制线粒体翻译可克服 AML 中的 Venetoclax 耐药性。
Sci Transl Med. 2019 Oct 30;11(516). doi: 10.1126/scitranslmed.aax2863.
6
Superior anti-tumor activity of the MDM2 antagonist idasanutlin and the Bcl-2 inhibitor venetoclax in p53 wild-type acute myeloid leukemia models.MDM2拮抗剂idasanutlin与Bcl-2抑制剂维奈托克在p53野生型急性髓系白血病模型中的卓越抗肿瘤活性。
J Hematol Oncol. 2016 Jun 28;9(1):50. doi: 10.1186/s13045-016-0280-3.
7
225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models.225Ac 标记的 CD33 靶向抗体逆转急性髓系白血病模型中对 Bcl-2 抑制剂 venetoclax 的耐药性。
Cancer Med. 2021 Feb;10(3):1128-1140. doi: 10.1002/cam4.3665. Epub 2020 Dec 21.
8
Combinatorial Inhibition of Focal Adhesion Kinase and BCL-2 Enhances Antileukemia Activity of Venetoclax in Acute Myeloid Leukemia.组合抑制黏着斑激酶和 BCL-2 增强 Venetoclax 对急性髓系白血病的抗白血病活性。
Mol Cancer Ther. 2020 Aug;19(8):1636-1648. doi: 10.1158/1535-7163.MCT-19-0841. Epub 2020 May 13.
9
Abivertinib synergistically strengthens the anti-leukemia activity of venetoclax in acute myeloid leukemia in a BTK-dependent manner.阿比替尼与维奈托克联合应用通过 BTK 依赖性途径增强急性髓系白血病的抗白血病活性。
Mol Oncol. 2020 Oct;14(10):2560-2573. doi: 10.1002/1878-0261.12742. Epub 2020 Jul 3.
10
Apoptosis targeted therapies in acute myeloid leukemia: an update.急性髓细胞白血病的凋亡靶向治疗：最新进展。
Expert Rev Hematol. 2020 Dec;13(12):1373-1386. doi: 10.1080/17474086.2020.1852923. Epub 2020 Dec 6.

引用本文的文献

1
Apoptosis-targeting BH3 mimetics: transforming treatment for patients with acute myeloid leukaemia.靶向凋亡的BH3模拟物：改变急性髓系白血病患者的治疗方式
Nat Rev Clin Oncol. 2025 Sep 1. doi: 10.1038/s41571-025-01068-0.
2
Cathepsin D promotes acute myeloid leukemia progression through stabilization of the anti-apoptotic proteins.组织蛋白酶D通过稳定抗凋亡蛋白促进急性髓系白血病进展。
Cell Death Dis. 2025 Aug 12;16(1):611. doi: 10.1038/s41419-025-07949-7.
3
Erythroid-predominant myelodysplastic neoplasms exhibit a distinct genomic landscape with poor outcomes after venetoclax-based therapy.

本文引用的文献

1
Wild-Type p53 Promotes Cancer Metabolic Switch by Inducing PUMA-Dependent Suppression of Oxidative Phosphorylation.野生型 p53 通过诱导 PUMA 依赖性的氧化磷酸化抑制促进癌症代谢转换。
Cancer Cell. 2019 Feb 11;35(2):191-203.e8. doi: 10.1016/j.ccell.2018.12.012. Epub 2019 Jan 31.
2
Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms.急性髓系白血病中因不同分子机制导致对克立硼烷耐药。
Nat Commun. 2019 Jan 16;10(1):244. doi: 10.1038/s41467-018-08263-x.
3
Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia.
以红系为主的骨髓增生异常肿瘤表现出独特的基因组格局，在接受基于维奈克拉的治疗后预后较差。
Leukemia. 2025 Jul 21. doi: 10.1038/s41375-025-02711-6.
4
Phase I first-in-human dose escalation study of the oral casein kinase 1α and cyclin dependent kinase 7/9 inhibitor BTX A51 in advanced MDS and AML.口服酪蛋白激酶1α和细胞周期蛋白依赖性激酶7/9抑制剂BTX A51用于晚期骨髓增生异常综合征和急性髓系白血病的I期首次人体剂量递增研究。
J Hematol Oncol. 2025 Jul 15;18(1):73. doi: 10.1186/s13045-025-01724-z.
5
Chemoresistance of TP53 mutant acute myeloid leukemia requires the mevalonate byproduct, geranylgeranyl pyrophosphate, for induction of an adaptive stress response.TP53突变型急性髓系白血病的化疗耐药需要甲羟戊酸副产物香叶基香叶基焦磷酸来诱导适应性应激反应。
Leukemia. 2025 Jul 9. doi: 10.1038/s41375-025-02668-6.
6
Efficacy and prognostic analysis of venetoclax combined with hypomethylating agents for induction therapy in acute myeloid leukemia: a multi-center real-world study on indication-specific stratification, molecular markers, and hematologic toxicities.维奈托克联合去甲基化药物用于急性髓系白血病诱导治疗的疗效及预后分析：一项关于适应证特异性分层、分子标志物和血液学毒性的多中心真实世界研究
Cancer Cell Int. 2025 Jul 1;25(1):241. doi: 10.1186/s12935-025-03858-z.
7
Identification of an Ara-C resistance-related gene risk score and the role of S100A4 in AML via NR6A1-dependent activation and p53 regulation.通过NR6A1依赖性激活和p53调节鉴定阿糖胞苷耐药相关基因风险评分及S100A4在急性髓系白血病中的作用
Front Pharmacol. 2025 Jun 13;16:1574759. doi: 10.3389/fphar.2025.1574759. eCollection 2025.
8
Hematopoietic Stem Cell Hierarchies As Novel Biomarkers of Drug Response in Myelodysplastic Syndromes and Acute Myeloid Leukemia.造血干细胞层级结构作为骨髓增生异常综合征和急性髓系白血病药物反应的新型生物标志物
Clin Cancer Res. 2025 Jun 26. doi: 10.1158/1078-0432.CCR-25-0591.
9
upregulation via aurora kinase inhibition overcomes primary failure to venetoclax in rearranged lymphomas.通过极光激酶抑制实现的上调克服了重排淋巴瘤中对维奈托克的原发性耐药。
iScience. 2025 May 2;28(6):112584. doi: 10.1016/j.isci.2025.112584. eCollection 2025 Jun 20.
10
Acquired resistance in cancer: towards targeted therapeutic strategies.癌症中的获得性耐药：靶向治疗策略研究
Nat Rev Cancer. 2025 Jun 3. doi: 10.1038/s41568-025-00824-9.
Mcl-1 特异性抑制剂 AZD5991 的发现及其在多发性骨髓瘤和急性髓系白血病中的临床前活性。
Nat Commun. 2018 Dec 17;9(1):5341. doi: 10.1038/s41467-018-07551-w.
4
GTRD: a database on gene transcription regulation-2019 update.GTRD：一个关于基因转录调控的数据库-2019 年更新。
Nucleic Acids Res. 2019 Jan 8;47(D1):D100-D105. doi: 10.1093/nar/gky1128.
5
Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells.抑制氨基酸代谢可选择性靶向杀伤人类白血病干细胞。
Cancer Cell. 2018 Nov 12;34(5):724-740.e4. doi: 10.1016/j.ccell.2018.10.005.
6
Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia.维奈托克联合地西他滨或阿扎胞苷治疗初治老年急性髓系白血病患者。
Blood. 2019 Jan 3;133(1):7-17. doi: 10.1182/blood-2018-08-868752. Epub 2018 Oct 25.
7
Functional genomic landscape of acute myeloid leukaemia.急性髓系白血病的功能基因组图谱。
Nature. 2018 Oct;562(7728):526-531. doi: 10.1038/s41586-018-0623-z. Epub 2018 Oct 17.
8
AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies.AMG 176，一种选择性 MCL1 抑制剂，在单独使用和与现有疗法联合使用时对血液系统癌症模型均有效。
Cancer Discov. 2018 Dec;8(12):1582-1597. doi: 10.1158/2159-8290.CD-18-0387. Epub 2018 Sep 25.
9
A Novel MCL1 Inhibitor Combined with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous Leukemia.一种新型 MCL1 抑制剂与 Venetoclax 联合可挽救 Venetoclax 耐药的急性髓系白血病。
Cancer Discov. 2018 Dec;8(12):1566-1581. doi: 10.1158/2159-8290.CD-18-0140. Epub 2018 Sep 5.
10
Oncogenic TRK fusions are amenable to inhibition in hematologic malignancies.致癌性 TRK 融合可抑制血液系统恶性肿瘤。
J Clin Invest. 2018 Aug 31;128(9):3819-3825. doi: 10.1172/JCI120787. Epub 2018 Aug 6.