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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 \u22640.4% of B-cell precursors and mature B cells from patients with MM and AL. Paired single-cell transcriptomes confirmed the immature phenotype of these clonotypic cells. Driver genetic alterations were primarily detected in tumor PCs 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 preneoplastic precursors of malignant PCs that are unlikely to be involved in disease progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>The cellular origin of MM and light-chain AL remains unknown. Here, we show that these tumors stem from clonotypic B cells, but driver genetic alterations are mainly contained within phenotypically aberrant PCs. These results shed light on the pathogenesis and inform on how to monitor PC neoplasms.<\/jats:p>\n                    <jats:p>See related commentary by Kim and Ghobrial, p. 503<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2643-3230.bcd-25-0102","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T20:42:45Z","timestamp":1773261765000},"page":"558-571","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic Evidence against Clonotypic B Lymphocytes as a Reservoir for Plasma-cell Cancers"],"prefix":"10.1158","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3074-9229","authenticated-orcid":false,"given":"Carmen","family":"Gonzalez","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02rxc7m23","id-type":"ROR","asserted-by":"publisher"}],"name":"Universidad de Navarra (CIMA) 1 Cancer Center Clinica Universidad de Navarra (CCUN), Centro de 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