Longitudinal single-cell analysis of a myeloma mouse model identifies subclonal molecular programs associated with progression

The molecular programs that underlie progression in multiple myeloma (MM) are incompletely understood. Here the authors use a mouse model of MM and single-cell RNA-seq to define subclonal expression programs that arise during progression and that inform targeted therapeutic strategies. Molecular programs that underlie precursor progression in multiple myeloma are incompletely understood. Here, we report a disease spectrum-spanning, single-cell analysis of the V kappa*MYC myeloma mouse model. Using samples obtained from mice with serologically undetectable disease, we identify malignant cells as early as 30 weeks of age and show that these tumours contain subclonal copy number variations that persist throughout progression. We detect intratumoural heterogeneity driven by transcriptional variability during active disease and show that subclonal expression programs are enriched at different times throughout early disease. We then show how one subclonal program related to GCN2 stress response is progressively activated during progression in myeloma patients. Finally, we use chemical and genetic perturbation of GCN2 in vitro to support this pathway as a therapeutic target in myeloma. These findings therefore present a model of precursor progression in V kappa*MYC mice, nominate an adaptive mechanism important for myeloma survival, and highlight the need for single-cell analyses to understand the biological underpinnings of disease progression.

Automated summary

The authors used a mouse model of multiple myeloma and single-cell RNA-seq to identify subclonal expression programs that arise during progression, providing insights for targeted therapeutic strategies. This study reveals intratumoural heterogeneity driven by transcriptional variability during active disease and highlights the importance of single-cell analyses in understanding the biological mechanisms of disease progression.