Single cell clonotypic and transcriptional evolution of multiple myeloma precursor disease

• Published in: Cancer cell 2023-06, Vol.41 (6), p.1032-1047.e4
• Main Authors: Dang, Minghao, Han, Guangchun, Lee, Hans C., Patel, Krina K., Becnel, Melody R., Wang, Ruiping, Thomas, Sheeba K., Hao, Dapeng, Chu, Yanshuo, Weber, Donna M., Lin, Pei, Lutter-Berka, Zuzana, Berrios Nolasco, David A., Huang, Mei, Bansal, Hima, Song, Xingzhi, Zhang, Jianhua, Futreal, Andrew, Moreno Rueda, Luz Yurany, Symer, David E., Green, Michael R., Rojas Hernandez, Cristhiam M., Kroll, Michael, Afshar-Khargan, Vahid, Ndacayisaba, Libere J., Kuhn, Peter, Neelapu, Sattva S., Orlowski, Robert Z., Wang, Linghua, Manasanch, Elisabet E.
• Format: Article
• Language: English
• Subjects: Aneuploidy; Biomedical Research; Disease Progression; Humans; hyperdiploid; intra-tumoral heterogeneity; monoclonal gammopathy of undetermined significance; multiple myeloma; Multiple Myeloma - genetics; non-hyperdiploid; single-cell B cell receptor sequencing; single-cell RNA sequencing; Smoldering Multiple Myeloma; tumor evolution; tumor microenvironment; Tumor Microenvironment - genetics
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2023.05.007

Multiple myeloma remains an incurable disease, and the cellular and molecular evolution from precursor conditions, including monoclonal gammopathy of undetermined significance and smoldering multiple myeloma, is incompletely understood. Here, we combine single-cell RNA and B cell receptor sequencing from fifty-two patients with myeloma precursors in comparison with myeloma and normal donors. Our comprehensive analysis reveals early genomic drivers of malignant transformation, distinct transcriptional features, and divergent clonal expansion in hyperdiploid versus non-hyperdiploid samples. Additionally, we observe intra-patient heterogeneity with potential therapeutic implications and identify distinct patterns of evolution from myeloma precursor disease to myeloma. We also demonstrate distinctive characteristics of the microenvironment associated with specific genomic changes in myeloma cells. These findings add to our knowledge about myeloma precursor disease progression, providing valuable insights into patient risk stratification, biomarker discovery, and possible clinical applications. [Display omitted] •Multiple myeloma precursors exhibit high degree of transcriptional heterogeneity•The HY and non-HY subtypes are transcriptionally and immunologically distinct•Early-stage tumors favor linear evolution; branching evolution arises with expansion Dang et al. present an in-depth analysis of the transcriptional landscapes in multiple myeloma precursors, revealing a high degree of transcriptional heterogeneity and distinct transcriptional and immunological characteristics of hyperdiploidy (HY) and non-HY subtypes. Integrating scRNA-seq and scBCR-seq, they elucidate transcriptional dynamics and evolutionary patterns in early disease.