Genetic evidence against clonotypic B-lymphocytes as reservoir of plasma-cell cancers
Whether multiple myeloma (MM) and light-chain amyloidosis (AL) stem from terminally differentiated plasma cells (PC) or earlier clonotypic B cells remains under debate. Addressing this issue would improve accurate diagnosis and treatment monitoring. We performed single-cell and exome sequencing on highly-purified MM and AL samples to define in which B-cell development stage the driver genetic alterations are present. Clonotypic B-cell receptors (BCR) were detected in ≤0.4% B-cell precursors and mature B cells from MM and AL patients. Paired single-cell transcriptomes confirmed the immature phenotype of these clonotypic cells. Driver genetic alterations were primarily detected in tumor PC but very rarely in immature B-cell stages sequenced during treatment. Additional analysis suggested that clonotypic B cells may sporadically result in false-positive minimal residual disease assessments based on next-generation sequencing of BCR. Our results define clonotypic B cells as pre-neoplastic precursors of malignant PC that are unlikely to be involved in disease progression.
Authors
- José A. Martínez-Climent (ORCID: https://orcid.org/0000-0002-7938-3950)
- Sarai Sarvide (ORCID: https://orcid.org/0000-0003-3528-9329)
- Felipe Prósper (ORCID: https://orcid.org/0000-0001-6115-8790)
- Diego Alignani (ORCID: https://orcid.org/0000-0003-0241-1375)
- Francesca Gay (ORCID: https://orcid.org/0000-0002-8619-412X)
- Margherita Massa (ORCID: https://orcid.org/0000-0001-8037-0439)
- Francesca Lattarulo (ORCID: https://orcid.org/0009-0009-8731-9340)
- Alice Nevone (ORCID: https://orcid.org/0000-0002-7724-1043)
- Giuseppe Bertuglia (ORCID: https://orcid.org/0009-0009-3785-9824)
- Marta Lasa (ORCID: https://orcid.org/0000-0002-2981-162X)
- José María Lamo-Espinosa (ORCID: https://orcid.org/0000-0002-9696-2620)
- H. Andreu Gracia (ORCID: https://orcid.org/0009-0004-3420-6231)
- Juan-José Garcés
- M. Teresa Álvarez Mateos
- Aitziber Lopez Lopez
- Bruno Paiva
- Noemí Puig
- Alejandro Medina-Herrera
- María-Teresa Cedena
- Jesus San-Miguel
- Mattia D´Agostino
- Joan Bladé
- Laura Rosinol
- Joaquin Martinez-Lopez
- Camila Guerrero
- Paula Rodriguez-Otero
- Carmen González
- Ramón García-Sanz
- Juan-Jose Lahuerta
- Paula Aguirre-Ruiz
- Giovannni Palladini
- Mario Nuvolone
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- University of Pavia (IT)
- Research Institute Hospital 12 de Octubre (ES)
- Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT)
- Complejo Hospitalario de Salamanca (ES)
- Hospital Universitario 12 De Octubre (ES)
- Hospital Clínic de Barcelona (ES)
- Instituto de Investigación Biomédica de Salamanca (ES)
- Clinica Universidad de Navarra (ES)
- Policlinico San Matteo Fondazione (IT)
- Universidad de Navarra (ES)
- Chartered Institute of Management Accountants (GB)
Publication Details
- Journal
- Blood Cancer Discovery
- Published
- 2026-03-11
- DOI
- https://doi.org/10.1158/2643-3230.bcd-25-0102
- Primary Topic
- Multiple Myeloma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00