Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell (PC) neoplasm that may evolve with variable frequency into multiple myeloma (MM). SMM is initiated by chromosomal translocations involving the immunoglobulin heavy-chain locus or by hyperdiploidy and evolves through acquisition of additional genetic lesions. In this scenario, we aimed at establishing a reliable analysis pipeline to infer genomic lesions from transcriptomic analysis, by combining single-cell RNA sequencing (scRNA-seq) with B-cell receptor sequencing and copy number abnormality (CNA) analysis to identify clonal PCs at the genetic level along their specific transcriptional landscape. We profiled 20 465 bone marrow PCs derived from 5 patients with SMM/MM and unbiasedly identified clonal and polyclonal PCs. Hyperdiploidy, t(11;14), and t(6;14) were identified at the scRNA level by analysis of chimeric reads. Subclone functional analysis was improved by combining transcriptome with CNA analysis. As examples, we illustrate the different functional properties of a light-chain escape subclone in SMM and of different B-cell and PC subclones in a patient affected by Wäldenstrom macroglobulinemia and SMM. Overall, our data provide a proof of principle for inference of clinically relevant genotypic data from scRNA-seq, which in turn will refine functional annotation of the clonal architecture of PC dyscrasias.

Inference of genomic lesions from single-cell RNA-seq in myeloma improves functional intraclonal and interclonal analysis / F. Lazzaroni, A. Matera, A. Marella, A. Maeda, G. Castellano, A. Marchetti, S. Fabris, S. Pioggia, I. Silvestris, D. Ronchetti, S. Lonati, G. Fabbiano, V. Traini, E. Taiana, L. Porretti, F. Colombo, C. De Magistris, M. Scopetti, M. Barbieri, L. Pettine, F. Torricelli, A. Neri, F. Passamonti, M. Lionetti, M.C. Da Vià, N. Bolli. - In: BLOOD ADVANCES. - ISSN 2473-9537. - 8:15(2024 Aug 13), pp. 3972-3984. [10.1182/bloodadvances.2023012409]

Inference of genomic lesions from single-cell RNA-seq in myeloma improves functional intraclonal and interclonal analysis

F. Lazzaroni
Co-primo
;
A. Matera
Co-primo
;
A. Marella
Secondo
;
A. Maeda;G. Castellano;A. Marchetti;S. Fabris;I. Silvestris;D. Ronchetti;S. Lonati;G. Fabbiano;V. Traini;E. Taiana;C. De Magistris;M. Scopetti;M. Barbieri;L. Pettine;A. Neri;F. Passamonti;M. Lionetti;N. Bolli
2024

Abstract

Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell (PC) neoplasm that may evolve with variable frequency into multiple myeloma (MM). SMM is initiated by chromosomal translocations involving the immunoglobulin heavy-chain locus or by hyperdiploidy and evolves through acquisition of additional genetic lesions. In this scenario, we aimed at establishing a reliable analysis pipeline to infer genomic lesions from transcriptomic analysis, by combining single-cell RNA sequencing (scRNA-seq) with B-cell receptor sequencing and copy number abnormality (CNA) analysis to identify clonal PCs at the genetic level along their specific transcriptional landscape. We profiled 20 465 bone marrow PCs derived from 5 patients with SMM/MM and unbiasedly identified clonal and polyclonal PCs. Hyperdiploidy, t(11;14), and t(6;14) were identified at the scRNA level by analysis of chimeric reads. Subclone functional analysis was improved by combining transcriptome with CNA analysis. As examples, we illustrate the different functional properties of a light-chain escape subclone in SMM and of different B-cell and PC subclones in a patient affected by Wäldenstrom macroglobulinemia and SMM. Overall, our data provide a proof of principle for inference of clinically relevant genotypic data from scRNA-seq, which in turn will refine functional annotation of the clonal architecture of PC dyscrasias.
Settore MEDS-09/B - Malattie del sangue
   spontaneous Evolution and Clonal heterOgeneity in MoNoclonal Gammopathies: from mechanisms of progression to clinical management (bECOMiNG)
   bECOMiNG
   EUROPEAN COMMISSION
   H2020
   817997
13-ago-2024
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1137716
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