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Título: | Differentiation stage of myeloma plasma cells: Biological and clinical significance |
Autor: | Paiva, Bruno; Puig, Noemi; Cedena, Maria-Teresa; Jong, B. G. de; Ruiz, Y.; Rapado, Inmaculada; Martínez-López, Joaquín; Cordón, Lourdes; Alignani, Diego; Delgado, J. A.; Zelm, Menno C. van; Dongen, J. J. M. van; Pascual, M.; Agirre, Xavier; Prósper, Felipe; Martín-Subero, José Ignacio; Vidriales, Maria Belén; Gutiérrez, Norma Carmen; Oriol, Albert; Echeveste, María-Asunción; González, Yolanda; Johnson, S. K.; Epstein, J.; Barlogie, B.; Morgan, Gareth J.; Orfao, Alberto CSIC ORCID ; Bladé, Joan; Mateos, Maria Victoria; Lahuerta, Juan José; Hernández, Mª Teresa; San Miguel, Jesús F. CSIC ORCID | Fecha de publicación: | 2017 | Editor: | Nature Publishing Group | Citación: | Leukemia 31(2): 382-392 (2017) | Resumen: | The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n=20) that the CD19-CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19-CD81+ and CD19-CD81- BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19-CD81-) clones, 38% intermediate-differentiated (CD19-CD81+) and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR: 1.7; P=0.005) and overall survival (HR: 2.1; P=0.006). Longitudinal comparison of diagnostic vs minimal-residual-disease samples (n=40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles. | Versión del editor: | https://doi.org/10.1038/leu.2016.211 | URI: | http://hdl.handle.net/10261/169182 | DOI: | 10.1038/leu.2016.211 | Identificadores: | doi: 10.1038/leu.2016.211 e-issn: 1476-5551 issn: 0887-6924 |
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