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Updated: Jun 23, 2025
An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells
Published on: July 15, 2015
Identification of Therapy-Induced Clonal Evolution and Resistance Pathways in Minimal Residual Clones in Multiple
Jian Cui1,2, Xiaoyun Li1,2, Shuhui Deng1,2,3
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China.
Purpose:
In multiple myeloma (MM), therapy-induced clonal evolution is associated with treatment resistance and is one of the most important hindrances toward a cure for MM. To further understand the molecular mechanisms controlling the clonal evolution of MM, we applied single-cell RNA sequencing (scRNA-seq) to paired diagnostic and posttreatment bone marrow (BM) samples.
Experimental Design:
scRNA-seq was performed on 38 BM samples from patients with monoclonal gammopathy of undetermined significance (n = 1), MM patients at diagnosis (n = 19), MM posttreatment (n = 17), and one healthy donor (HD). The single-cell transcriptome data of malignant plasma cells (PC) and the surrounding immune microenvironment were analyzed.
Results:
Profiling by scRNA-seq data revealed three primary trajectories of transcriptional evolution after treatment: clonal elimination in patients with undetectable minimal residual disease (MRD-) and clonal stabilization and clonal selection in detectable MRD (MRD+) patients. We noted a metabolic shift toward fatty acid oxidation in cycling-resistant PCs, whereas selective PCs favored the NF-κB pathway. Intriguingly, when comparing the genetic and transcriptional dynamics, we found a significant correlation between genetic and nongenetic factors in driving the clonal evolution. Furthermore, we identified variations in cellular interactions between malignant PCs and the tumor microenvironment. Selective PCs showed the most robust cellular interactions with the tumor microenvironment.
Conclusions:
These data suggest that MM cells could rapidly adapt to induction treatment through transcriptional adaptation, metabolic adaptation, and specialized immune evasion. Targeting therapy-induced resistance mechanisms may help to avert refractory disease in MM.
Insights
Multiple myeloma cells adapt to treatment via transcriptional and metabolic changes, leading to resistance. Targeting these adaptations may help overcome refractory disease in multiple myeloma (MM).
Area of Science:
- Hematology
- Oncology
- Genomics
- Immunology
Background:
- Therapy-induced clonal evolution in multiple myeloma (MM) drives treatment resistance, hindering curative strategies.
- Understanding the molecular mechanisms of MM clonal evolution is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the molecular mechanisms underlying clonal evolution in multiple myeloma (MM) following treatment.
- To analyze transcriptional and cellular changes in malignant plasma cells (PCs) and their microenvironment using single-cell RNA sequencing (scRNA-seq).
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) was performed on bone marrow (BM) samples from patients with monoclonal gammopathy of undetermined significance, MM at diagnosis, MM posttreatment, and healthy donors.
- Transcriptome data from malignant plasma cells (PCs) and the immune microenvironment were analyzed to identify evolutionary trajectories.
Main Results:
- Three distinct evolutionary trajectories were observed post-treatment: clonal elimination (MRD-), clonal stabilization, and clonal selection (MRD+).
- Resistant PCs exhibited a metabolic shift towards fatty acid oxidation and favored the NF-κB pathway.
- Genetic and non-genetic factors significantly correlated in driving clonal evolution, with selective PCs showing enhanced interactions with the tumor microenvironment.
Conclusions:
- Multiple myeloma cells demonstrate rapid adaptation to induction treatment through transcriptional, metabolic, and immune evasion mechanisms.
- Targeting therapy-induced resistance pathways is a potential strategy to prevent refractory disease in multiple myeloma.
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