Detalle Publicación

ARTÍCULO
Differentiation stage of myeloma plasma cells: biological and clinical significance
Autores: Paiva, Bruno; Puig, N.; Cedena, M. T.; de Jong, B. G.; Ruiz, Y.; Rapado, I.; Martinez-Lopez, J.; Cordon, L.; Alignani, Diego Oscar; Delgado García, José Antonio; van Zelm, M. C.; van Dongen, J. J. M.; Pascual De Pedro, Marién; Aguirre Ena, Xabier; Prosper Cardoso, Felipe; Martin-Subero, J. I.; Vidriales, M. B.; Gutierrez, N. C.; Hernandez, M. T.; Oriol, A.; Echeveste, M. A.; Gonzalez, Y.; Johnson, S. K.; Epstein, J.; Barlogie, B.; Morgan, G. J.; Orfao, A.; Blade, J.; Mateos, M. V.; Lahuerta, J. J.; San Miguel Izquierdo, Jesús
Título de la revista: LEUKEMIA
ISSN: 0887-6924
Volumen: 31
Número: 2
Páginas: 382 - 392
Fecha de publicación: 2017
Lugar: WOS
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.