Multiple myeloma (MM) is a haematological malignancy characterized by the clonal expansion of immunoglobulin-secreting plasma cells in the bone marrow (BM) 1. These findings therefore present a model of precursor progression in Vκ*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. Finally, we use chemical and genetic perturbation of GCN2 in vitro to support this pathway as a therapeutic target in myeloma. We then show how one subclonal program related to GCN2 stress response is progressively activated during progression in myeloma patients. 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. 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. Here, we report a disease spectrum-spanning, single-cell analysis of the Vκ*MYC myeloma mouse model. Molecular programs that underlie precursor progression in multiple myeloma are incompletely understood.

Pro line 20 express