Single cell characterization of myeloma and its precursor conditions reveals transcriptional signatures of early tumorigenesis

Rebecca Boiarsky, Nicholas J. Haradhvala, Jean-Baptiste Alberge, Romanos Sklavenitis-Pistofidis, Tarek H. Mouhieddine, Oksana Zavidij, Ming-Chieh Shih, Danielle Firer, Mendy Miller, Habib El-Khoury, Shankara K. Anand, François Aguet, David Sontag (), Irene M. Ghobrial () and Gad Getz ()
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Rebecca Boiarsky: Broad Institute of MIT and Harvard
Nicholas J. Haradhvala: Broad Institute of MIT and Harvard
Jean-Baptiste Alberge: Broad Institute of MIT and Harvard
Romanos Sklavenitis-Pistofidis: Broad Institute of MIT and Harvard
Tarek H. Mouhieddine: Icahn School of Medicine at Mount Sinai
Oksana Zavidij: Constellation Pharmaceuticals a MorphoSys Company
Ming-Chieh Shih: CSAIL and IMES, Massachusetts Institute of Technology
Danielle Firer: Broad Institute of MIT and Harvard
Mendy Miller: Broad Institute of MIT and Harvard
Habib El-Khoury: Dana-Farber Cancer Institute
Shankara K. Anand: Broad Institute of MIT and Harvard
François Aguet: Broad Institute of MIT and Harvard
David Sontag: Broad Institute of MIT and Harvard
Irene M. Ghobrial: Broad Institute of MIT and Harvard
Gad Getz: Broad Institute of MIT and Harvard

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Multiple myeloma is a plasma cell malignancy almost always preceded by precursor conditions, but low tumor burden of these early stages has hindered the study of their molecular programs through bulk sequencing technologies. Here, we generate and analyze single cell RNA-sequencing of plasma cells from 26 patients at varying disease stages and 9 healthy donors. In silico dissection and comparison of normal and transformed plasma cells from the same bone marrow biopsy enables discovery of patient-specific transcriptional changes. Using Non-Negative Matrix Factorization, we discover 15 gene expression signatures which represent transcriptional modules relevant to myeloma biology, and identify a signature that is uniformly lost in abnormal cells across disease stages. Finally, we demonstrate that tumors contain heterogeneous subpopulations expressing distinct transcriptional patterns. Our findings characterize transcriptomic alterations present at the earliest stages of myeloma, providing insight into the molecular underpinnings of disease initiation.

Date: 2022
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DOI: 10.1038/s41467-022-33944-z

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