Journal Article Epublish
PubMed: 40399990 DOI: 10.1186/s12967-025-06615-y
Establishment of a prognostic model based on ER stress-related cell death genes and proposing a novel combination therapy in acute myeloid leukemia.
J Transl Med 23(1):566
Authors: Minghui Wang, Huajian Xian, Xiaoli Xia, Wenjie Zhang, Zixuan Huang, Chaoqun Lu, Yuling Zheng, Yixin Wang, Shufeng Xie, Renyao Pan, YaoYifu Yu, Ruiheng Wang, Huijian Zheng, Guorui Huang, Han Liu
Affiliations
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
Abstract
BACKGROUND
Acute myeloid leukemia (AML) is a highly heterogeneous malignancy, presenting significant challenges in accurately predicting patient prognosis. Dysregulation of endoplasmic reticulum (ER) stress and resistance to programmed cell death (PCD) are hallmarks of AML cells. However, the prognostic significance of the interplay between ER stress and cell death pathways in AML remains largely unexplored.
METHODS
We analyzed RNA sequencing and clinical data from 887 AML patients across 4 cohorts to develop an ER stress-related cell death index (ERCDI) using 10 machine-learning algorithms with 117 unique combinations. Survival and time-dependent Receiver Operating Characteristic Curve (ROC) analyses were performed to assess the model's efficacy. Clinical characteristics, the tumor immune microenvironment, and drug sensitivity differences between the high- and low-risk groups were also analyzed. The CMap database was used to identify potential therapeutic drugs. In vitro and in vivo experiments, including CCK-8, colony formation, flow cytometry, Transwell assays, and xenograft mouse models, were conducted to evaluate the effects of the target genes and candidate drugs.
RESULTS
The ERCDI demonstrated strong prognostic and predictive performance for prognosis in AML patients. Furthermore, the ERCDI effectively predicted immunotherapy and chemotherapy outcomes and was associated with the immune features of the different risk groups. DNA damage-inducible transcript 4 protein (DDIT4), a key gene associated with ERCDI, is related to poor prognosis in AML patients with high expression. Additionally, the knockdown of DDIT4 significantly inhibited AML cell proliferation, induced cell apoptosis, and promoted cell cycle arrest. Chaetocin was subsequently identified as a candidate compound for AML treatment. Subsequent experiments suggested that combining chaetocin and venetoclax is a potentially promising therapeutic strategy for AML.
CONCLUSION
The ERCDI provides personalized risk assessment and treatment recommendations for individual AML patients. The combined use of chaetocin and venetoclax can potentially be repurposed for AML therapy.
MeSH
Cells, Genes, Biomedical Research, Pharmaceutical Preparations, Stress, Physiological, Neoplasms, Leukemia, Leukemia, Myeloid, Acute, Leukemia, Myeloid, Therapeutics, Cell Death, Roc Curve, Prognosis