Abstract
Molecular programs that underlie precursor progression in multiple myeloma are incompletely understood. Here, we report a disease spectrum-spanning, single-cell analysis of the Vκ*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 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.
Highlights
Molecular programs that underlie precursor progression in multiple myeloma are incompletely understood
These analyses reveal that the malignant cell compartment of mice with early disease consists of multiple copy number variations (CNVs)-driven subpopulations and is enriched for transcriptional programs identified as subclonal in mice with activeMM
To model the evolutionary stages of human MM disease progression, we established a cohort of Vκ*MYC mice on the C57BL/6/KaLwRij background strain (Fig. 1a and Supplementary Data 1), which has been shown to have an increased propensity for developing spontaneous monoclonal gammopathies[24,25]
Summary
Molecular programs that underlie precursor progression in multiple myeloma are incompletely understood. We use chemical and genetic perturbation of GCN2 in vitro to support this pathway as a therapeutic target in myeloma These findings 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. Previous attempts to unravel the molecular underpinnings of disease progression in myeloma have relied on the use of bulk genomic sequencing[6,7,8,9] and transcriptional analyses[10,11] These studies have shown that the genomic landscape of precursor myeloma is similar to active disease but reveals a handful of aberrations that are more commonly identified in precursor patients that progress (i.e., high-risk precursor disease) including dysregulation of MYC, MAPK, and DNA repair pathways[7]. The Vκ*MYC model provides a unique opportunity to assess the molecular profiles of malignant cells from the earliest stages of myeloma, prior to serological detection of disease, which is typically not feasible in human studies
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