Related Experiment Video
Updated: May 9, 2025
Heterogeneity Mapping of Protein Expression in Tumors using Quantitative Immunofluorescence
Published on: October 25, 2011
Leveraging a disulfidptosis-based signature to characterize heterogeneity and optimize treatment in multiple myeloma
Bingxin Zhang1, Dong Zheng1, Shuxia Zhu1
1Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Background:
Disulfidptosis is an emerging type of programmed cell death related to ROS accumulation and aberrant disulfide bond formation. Multiple myeloma (MM) is the second most prevalent hematologic malignancy characterized by a high synthesis rate of disulfide bond-rich proteins and chronic oxidative stress. However, the relationship between disulfidptosis and MM is still unclear.
Methods:
Using the non-negative matrix factorization and lasso algorithm, we constructed the disulfidptosis-associated subtypes and the prognostic model on the GEO dataset. We further explored genetic mutation mapping, protein-protein interactions, functional enrichment, drug sensitivity, drug prediction, and immune infiltration analysis among subtypes and risk subgroups. To improve the clinical benefits, we combined risk scores and clinical metrics to build a nomogram. Finally, in vitro experiments examined the expression patterns of disulfidptosis-related genes (DRGs) in MM.
Results:
By cluster analysis, we obtained three subtypes with C2 having a worse prognosis than C3. Consistently, C2 exhibited significantly lower sensitivity to doxorubicin and lenalidomide, as well as a higher propensity for T-cell depletion and a non-responsive state to immunotherapy. Similarly, in the subsequent prognostic model, the high-scoring group had a worse prognosis and a higher probability of T-cell dysfunction, immunotherapy resistance, and cancer cell self-renewal. DRGs and risk genes were widely mutated in cancers. Subtypes and risk subgroups differed in ROS metabolism and the p53 signaling pathway. We further identified eight genes differentially expressed in risk subgroups as drug targets against MM. Then 27 drugs targeting the high-risk group were predicted. Based on the DRGs and risk genes, we constructed the miRNA and TF regulatory networks. The nomogram of combined ISS, age, and risk score showed good predictive performance. qRT-PCR of cell lines and clinical specimens provided further support for prognostic modeling.
Conclusion:
Our research reveals the prognostic value of disulfidptosis in MM and provides new perspectives for identifying heterogeneity and therapeutic targets.
Insights
Disulfidptosis, a cell death pathway linked to oxidative stress, is explored in multiple myeloma (MM). This study identifies MM subtypes and develops a prognostic model, revealing potential therapeutic targets and improving patient stratification for better treatment outcomes.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Disulfidptosis is a programmed cell death mechanism associated with reactive oxygen species (ROS) and disulfide bond abnormalities.
- Multiple myeloma (MM) is a hematologic malignancy with high protein synthesis, chronic oxidative stress, and unclear links to disulfidptosis.
Purpose of the Study:
- To investigate the relationship between disulfidptosis and multiple myeloma.
- To identify disulfidptosis-associated subtypes and develop a prognostic model for MM.
- To explore potential therapeutic targets and improve clinical management of MM.
Main Methods:
- Non-negative matrix factorization and lasso algorithm were used to construct MM subtypes and a prognostic model.
- Analysis included genetic mutations, protein-protein interactions, functional enrichment, drug sensitivity, and immune infiltration.
- A nomogram combining risk scores and clinical metrics was developed, with in vitro validation of disulfidptosis-related genes (DRGs).
Main Results:
- Three MM subtypes were identified, with one subtype showing a worse prognosis, lower drug sensitivity, and T-cell depletion.
- The prognostic model indicated that high-risk groups had poorer outcomes, T-cell dysfunction, and immunotherapy resistance.
- Differentially expressed genes were identified as potential drug targets, and regulatory networks were constructed.
Conclusions:
- Disulfidptosis plays a significant prognostic role in multiple myeloma.
- This research offers novel insights into MM heterogeneity and identifies potential therapeutic targets.
- The findings support improved patient stratification and personalized treatment strategies for MM.
