Aberrant single-cell phenotype and clinical implications of genotypically defined polyclonal plasma cells in myeloma

Multiple myeloma (MM) is driven by clonal plasma cell (cPC)-intrinsic factors and changes in the tumor microenvironment (TME). To investigate whether residual polyclonal PCs (pPCs) are disrupted, single-cell (sc) RNA sequencing (scRNA-seq) and sc B-cell receptor analysis were applied in a cohort of 46 samples with PC dyscrasias and 21 healthy donors (HDs). Of 234 789 PCs, 64 432 were genotypically identified as pPCs with frequencies decreasing over different disease stages, from 23.66% in monoclonal gammopathy of undetermined significance to 3.23% in MMs (P = .00012). Both cPCs and pPCs had a comparable expression of typical lineage markers (ie, CD38 and CD138), whereas others were more variable (CD27 and ITGB7). Only cPCs overexpressed oncogenes (eg, CCND1/2 and NSD2), but CCND3 was often expressed in pPCs. B-cell maturation antigen was expressed on both pPCs and cPCs, whereas GPRC5D was mostly upregulated in cPCs with implications for on-target, off-tumor activity of targeted immunotherapies. In comparison with HDs, pPCs from patients showed upregulated autophagy and disrupted interaction with TME. Importantly, interferon-related pathways were significantly enriched in pPCs from patients vs HDs (adjusted P < .05) showing an inflamed phenotype affecting genotypically normal PCs. The function of pPCs was consequently affected and correlated with immunoparesis, driven by disrupted cellular interactions with TME. Leveraging our scRNA-seq data, we derived a "healthy PC signature" that could be applied to bulk transcriptomics from the CoMMpass data set and predicted significantly better progression-free survival and overall survival (log-rank P < .05 for both). Our findings show that genotypic sc identification of pPCs in PC dyscrasias has relevant pathogenic and clinical implications.

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Journal
Blood
Published
2025-02-26
DOI
https://doi.org/10.1182/blood.2024025643
Citations
9
Primary Topic
Multiple Myeloma Research and Treatments
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article
Field-Weighted Citation Impact
15.93
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article

Aberrant single-cell phenotype and clinical implications of genotypically defined polyclonal plasma cells in myeloma

Francesca Lazzaroni, Alessio Marella, Cathelijne Fokkema, Francesco Passamonti et al.
9 citations
Blood
Multiple Myeloma Research and Treatments
15.93
article

Aberrant single-cell phenotype and clinical implications of genotypically defined polyclonal plasma cells in myeloma

Francesca Lazzaroni, Alessio Marella, Cathelijne Fokkema, Francesco Passamonti, Giancarlo Castellano, Marzia Barbieri, Antonio Matera, Silvia Lonati, Claudio De Magistris, Riccardo Giorgino, E Calvi, Federica Torricelli, Antonino Neri, Niccolò Bolli, Loredana Pettine, Marta Lionetti, Stefania Pioggia, Sonia Fabris, Antonio Giovanni Solimando, G. Peretti, Tom Cupedo, Akihiro Maeda, Matteo Da Vià, Alfredo Marchetti, Vanessa Desantis, Laura Mangiavini, Alessandra Cattaneo, Marta Tornese, Margherita Scopetti, Nayyer Latifinavid
article en
9 citations

Abstract

Multiple myeloma (MM) is driven by clonal plasma cell (cPC)-intrinsic factors and changes in the tumor microenvironment (TME). To investigate whether residual polyclonal PCs (pPCs) are disrupted, single-cell (sc) RNA sequencing (scRNA-seq) and sc B-cell receptor analysis were applied in a cohort of 46 samples with PC dyscrasias and 21 healthy donors (HDs). Of 234 789 PCs, 64 432 were genotypically identified as pPCs with frequencies decreasing over different disease stages, from 23.66% in monoclonal gammopathy of undetermined significance to 3.23% in MMs (P = .00012). Both cPCs and pPCs had a comparable expression of typical lineage markers (ie, CD38 and CD138), whereas others were more variable (CD27 and ITGB7). Only cPCs overexpressed oncogenes (eg, CCND1/2 and NSD2), but CCND3 was often expressed in pPCs. B-cell maturation antigen was expressed on both pPCs and cPCs, whereas GPRC5D was mostly upregulated in cPCs with implications for on-target, off-tumor activity of targeted immunotherapies. In comparison with HDs, pPCs from patients showed upregulated autophagy and disrupted interaction with TME. Importantly, interferon-related pathways were significantly enriched in pPCs from patients vs HDs (adjusted P < .05) showing an inflamed phenotype affecting genotypically normal PCs. The function of pPCs was consequently affected and correlated with immunoparesis, driven by disrupted cellular interactions with TME. Leveraging our scRNA-seq data, we derived a "healthy PC signature" that could be applied to bulk transcriptomics from the CoMMpass data set and predicted significantly better progression-free survival and overall survival (log-rank P < .05 for both). Our findings show that genotypic sc identification of pPCs in PC dyscrasias has relevant pathogenic and clinical implications.

BloodVol. 145(26)
University of Milan (IT), Erasmus MC (NL), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Ospedale Maggiore (IT), Azienda Sanitaria Unità Locale di Reggio Emilia (IT), IRCCS Ospedale Galeazzi - Sant'Ambrogio (IT), Erasmus MC Cancer Institute (NL), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University of Bari Aldo Moro (IT)
Good health and well-being
Openalex Percentile: Top 1%
Multiple Myeloma Research and Treatments
15.93
DOIOpen Access PDFOpenAlex
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