Genetic evidence against clonotypic B-lymphocytes as reservoir of plasma-cell cancers

Mar 11, 2026 | Magazine: Blood Cancer Discovery

Carmen González 1, Juan-Jose Garces 2, Hector Gracia 3, Camila Guerrero 4, Mattia D Agostino 5, Alejandro Medina-Herrera 6, Mario Nuvolone 7, Noemi Puig 6, María-Teresa Cedena 8, Marta Lasa 9, Diego Alignani 10, Aitziber Lopez 11, Sarai Sarvide 10, Paula Aguirre-Ruiz 10, José Maria Lamo-Espinosa 10, Felipe Prosper 10, Paula Rodriguez-Otero 10, Jose A Martinez-Climent 4, Francesca Lattarulo 7, Alice Nevone 12, Margherita Massa 13, Giovannni Palladini 7, Giuseppe Bertuglia 14, Francesca Gay 15, Laura Rosinol 16, Ramón García-Sanz 17, Joaquin Martinez-Lopez 18, Maria-Victoria Mateos 19, Juan-Jose Lahuerta 8, Joan Bladé 20, Jesus F San-Miguel 21, Bruno Paiva 22

Abstract

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.

CITA DEL ARTÍCULO Blood Cancer Discov. 2026 Mar 11. doi: 10.1158/2643-3230.BCD-25-0102. Online ahead of print.

see publication in pubmed