Differentiation stage of myeloma plasma cells: biological and clinical significance
Paiva B (1), Puig N (2), Cedena MT (3), de Jong BG (4), Ruiz Y (3), Rapado I (3), Martinez-Lopez J (3), Cordon L (5), Alignani D (1), Delgado JA (1), van Zelm MC (4,6), Van Dongen JJ (4), Pascual M ()1, Aguirre X (1), Prosper F (1), Martín-Subero JI (7), Vidriales MB (2), Gutierrez NC (2), Hernandez MT (8), Oriol A (9), Echeveste MA (10), Gonzalez Y (11), Johnson SK (12), Epstein J (12), Barlogie B (12), Morgan GJ (12), Orfao A (13), Blade J (14), Mateos MV (2), Lahuerta JJ (3), Miguel JF (1).
(1) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA, Pamplona.
(2) Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca.
(3) Hospital 12 de Octubre, Madrid.
(4) Department of Immunology, Erasmus MC, University Medical Center, Rotterdam.
(5) Hospital Universitario y Politécnico La Fe, Valencia.
(6) Department of Immunology and Pathology, Monash University, Melbourne, VIC, Australia.
(7) Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
(8) Hospital Universitario de Canarias, Tenerife.
(9) Institut Català d'Oncologia, Institut Josep Carreras, Hospital Germans Trias I Pujol, Badalona.
(10) Hospital de Donostia, San Sebastian.
(11) Hospital Universitario Josep Trueta, Girona.
(12) Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR.
(13) Servicio General de Citometría, Centro de Investigación del Cancer (IBMCC-USAL, CSIC), IBSAL and Department of Medicine, Universidad de Salamanca, Salamanca.
(14) Hospital Clínic, IDIBAPS, Barcelona, Spain.
Date: Aug 1, 2016Haematology and Hameotherapy
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 (e.g.: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 harboring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles.
CITATION Leukemia. 2016 Aug 1. doi: 10.1038/leu.2016.211
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