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Updated: Jul 25, 2025
An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells
Published on: July 15, 2015
Resolving therapy resistance mechanisms in multiple myeloma by multiomics subclone analysis
Alexandra M Poos1,2, Nina Prokoph1,2, Moritz J Przybilla3,4,5
1Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
Abstract:
Intratumor heterogeneity as a clinical challenge becomes most evident after several treatment lines, when multidrug-resistant subclones accumulate. To address this challenge, the characterization of resistance mechanisms at the subclonal level is key to identify common vulnerabilities. In this study, we integrate whole-genome sequencing, single-cell (sc) transcriptomics (scRNA sequencing), and chromatin accessibility (scATAC sequencing) together with mitochondrial DNA mutations to define subclonal architecture and evolution for longitudinal samples from 15 patients with relapsed or refractory multiple myeloma. We assess transcriptomic and epigenomic changes to resolve the multifactorial nature of therapy resistance and relate it to the parallel occurrence of different mechanisms: (1) preexisting epigenetic profiles of subclones associated with survival advantages, (2) converging phenotypic adaptation of genetically distinct subclones, and (3) subclone-specific interactions of myeloma and bone marrow microenvironment cells. Our study showcases how an integrative multiomics analysis can be applied to track and characterize distinct multidrug-resistant subclones over time for the identification of molecular targets against them.
Insights
Understanding cancer
Area of Science:
- Cancer Biology
- Genomics
- Epigenetics
Background:
- Intratumor heterogeneity poses a significant clinical challenge, particularly in relapsed or refractory multiple myeloma.
- Multidrug-resistant subclones accumulate after multiple treatment lines, necessitating a deeper understanding of resistance mechanisms.
Purpose of the Study:
- To characterize subclonal architecture and evolution in multiple myeloma.
- To identify common vulnerabilities and molecular targets by analyzing resistance mechanisms at the subclonal level.
Main Methods:
- Integration of whole-genome sequencing, single-cell (sc) transcriptomics (scRNA sequencing), and single-cell chromatin accessibility (scATAC sequencing).
- Analysis of mitochondrial DNA mutations and longitudinal samples from 15 patients with relapsed or refractory multiple myeloma.
Main Results:
- Characterization of subclonal evolution and the multifactorial nature of therapy resistance.
- Identification of preexisting epigenetic profiles, converging phenotypic adaptations, and subclone-specific microenvironment interactions contributing to resistance.
Conclusions:
- Integrative multiomics analysis effectively tracks multidrug-resistant subclones over time.
- This approach aids in identifying novel molecular targets for overcoming therapy resistance in multiple myeloma.
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