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已发表论文
急性髓系白血病发展与管理中整合应激反应的当前认知：一个前景可期的新靶点
Authors Jiang W , Hong Y , Wang P , Yang X , Shao K, Li M , Wu D
Received 15 October 2025
Accepted for publication 10 December 2025
Published 17 December 2025 Volume 2025:19 Pages 11269—11288
DOI https://doi.org/10.2147/DDDT.S573043
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Anastasios Lymperopoulos
Wanzhi Jiang,1,2,* Yaonan Hong,1,2,* Peicheng Wang,1,2,* Xiawan Yang,1– 3 Keding Shao,4 Man Li,1,5 Dijiong Wu1– 3,6
1Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, People’s Republic of China; 2The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3National Traditional Chinese Medicine Clinical Research Base (Hematology), Hangzhou, Zhejiang, People’s Republic of China; 4Office of Academic Research, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 5Department of Pharmacy, The First Hospital of Jiaxing & First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, People’s Republic of China; 6Department of Oncology and Hematology, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Zhejiang Chinese Medicine University, Wenzhou, Zhejiang, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Dijiong Wu, Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310006, People’s Republic of China, Tel +86-0571-86620325, Email wudijiong@zcmu.edu.cn Man Li, Department of Pharmacy, The First Hospital of Jiaxing & First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, 314000, People’s Republic of China, Email liman1451098759@163.com
Abstract: Primary or acquired resistance to standard chemotherapy and novel targeted therapies remains a common cause of relapsed/refractory acute myeloid leukemia (AML). The five-year overall survival rate for AML patients remains poor. Exploring novel therapeutic pathways may offer effective strategies to address this challenge. The Integrated Stress Response (ISR) is a signaling pathway that maintains cellular homeostasis by reducing global protein synthesis in response to external and internal stressors. Recent studies have demonstrated that ISR exerts a dual role in AML. Moderate activation of ISR supports hematopoietic and leukemia stem cell maintenance and promotes AML progression, whereas hyperactivation of ISR induces apoptosis and reduces myeloid cell leukemia-1 (MCL-1) expression. MCL-1 overexpression contributes to venetoclax resistance. However, MCL-1 inhibitors have shown disappointing cardiac toxicity in clinical studies. Hyperactivation of the ISR can indirectly suppress MCL-1 and help reverse venetoclax (ABT-199) resistance, as reported in previous studies. Our previous study also indicates that ISR activation can reverse venetoclax resistance in AML cells. These findings support the ISR as a novel therapeutic target in AML. However, the mechanisms by which ISR influences stemness and resistance are not yet fully understood. This review integrates current mechanistic insights and preclinical evidence to highlight the ISR as both a key driver of leukemogenesis and a promising target for overcoming drug resistance in AML. We searched the literature up to October 2025 in PubMed, Google Scholar, and ClinicalTrials.gov using terms related to AML, ISR signaling, venetoclax, and ISR kinases.
Keywords: acute myeloid leukemia, integrated stress response, eIF2α, ATF4, resistance
1Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, People’s Republic of China; 2The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3National Traditional Chinese Medicine Clinical Research Base (Hematology), Hangzhou, Zhejiang, People’s Republic of China; 4Office of Academic Research, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 5Department of Pharmacy, The First Hospital of Jiaxing & First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, People’s Republic of China; 6Department of Oncology and Hematology, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Zhejiang Chinese Medicine University, Wenzhou, Zhejiang, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Dijiong Wu, Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310006, People’s Republic of China, Tel +86-0571-86620325, Email wudijiong@zcmu.edu.cn Man Li, Department of Pharmacy, The First Hospital of Jiaxing & First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, 314000, People’s Republic of China, Email liman1451098759@163.com
Abstract: Primary or acquired resistance to standard chemotherapy and novel targeted therapies remains a common cause of relapsed/refractory acute myeloid leukemia (AML). The five-year overall survival rate for AML patients remains poor. Exploring novel therapeutic pathways may offer effective strategies to address this challenge. The Integrated Stress Response (ISR) is a signaling pathway that maintains cellular homeostasis by reducing global protein synthesis in response to external and internal stressors. Recent studies have demonstrated that ISR exerts a dual role in AML. Moderate activation of ISR supports hematopoietic and leukemia stem cell maintenance and promotes AML progression, whereas hyperactivation of ISR induces apoptosis and reduces myeloid cell leukemia-1 (MCL-1) expression. MCL-1 overexpression contributes to venetoclax resistance. However, MCL-1 inhibitors have shown disappointing cardiac toxicity in clinical studies. Hyperactivation of the ISR can indirectly suppress MCL-1 and help reverse venetoclax (ABT-199) resistance, as reported in previous studies. Our previous study also indicates that ISR activation can reverse venetoclax resistance in AML cells. These findings support the ISR as a novel therapeutic target in AML. However, the mechanisms by which ISR influences stemness and resistance are not yet fully understood. This review integrates current mechanistic insights and preclinical evidence to highlight the ISR as both a key driver of leukemogenesis and a promising target for overcoming drug resistance in AML. We searched the literature up to October 2025 in PubMed, Google Scholar, and ClinicalTrials.gov using terms related to AML, ISR signaling, venetoclax, and ISR kinases.
Keywords: acute myeloid leukemia, integrated stress response, eIF2α, ATF4, resistance