title: Differentiation stage of myeloma plasma cells: biological and clinical significance.
abstract: 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.
authors.affiliation: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA, Pamplona, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Paiva
authors.affiliation: Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Puig
authors.affiliation: Hospital 12 de Octubre, Madrid, Spain.
authors.forename: M T
authors.initials: MT
authors.lastname: Cedena
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
authors.forename: B G
authors.initials: BG
authors.lastname: de Jong
authors.affiliation: Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Y
authors.initials: Y
authors.lastname: Ruiz
authors.affiliation: Hospital 12 de Octubre, Madrid, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Rapado
authors.affiliation: Hospital 12 de Octubre, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Martinez-Lopez
authors.affiliation: Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Cordon
authors.affiliation: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA, Pamplona, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Alignani
authors.affiliation: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA, Pamplona, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Delgado
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.|Department of Immunology and Pathology, Monash University, Melbourne VIC Australia.
authors.forename: M C
authors.initials: MC
authors.lastname: van Zelm
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
authors.forename: J J M
authors.initials: JJ
authors.lastname: Van Dongen
authors.affiliation: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA, Pamplona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Pascual
authors.affiliation: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA, Pamplona, Spain.
authors.forename: X
authors.initials: X
authors.lastname: Agirre
authors.affiliation: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA, Pamplona, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Prosper
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: J I
authors.initials: JI
authors.lastname: Martín-Subero
authors.affiliation: Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain.
authors.forename: M-B
authors.initials: MB
authors.lastname: Vidriales
authors.affiliation: Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain.
authors.forename: N C
authors.initials: NC
authors.lastname: Gutierrez
authors.affiliation: Hospital Universitario de Canarias, Tenerife, Spain.
authors.forename: M T
authors.initials: MT
authors.lastname: Hernandez
authors.affiliation: Institut Català d'Oncologia, Institut Josep Carreras, Hospital Germans Trias I Pujol, Badalona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Oriol
authors.affiliation: Hospital de Donostia, San Sebastian, Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: Echeveste
authors.affiliation: Hospital Universitario Josep Trueta, Girona, Spain.
authors.forename: Y
authors.initials: Y
authors.lastname: Gonzalez
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Johnson
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: J
authors.initials: J
authors.lastname: Epstein
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: B
authors.initials: B
authors.lastname: Barlogie
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Morgan
authors.affiliation: Servicio General de Citometría, Centro de Investigación del Cancer (IBMCC-USAL, CSIC), IBSAL and Department of Medicine, Universidad de Salamanca, Salamanca, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Orfao
authors.affiliation: Hospital Clínic, IDIBAPS, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Blade
authors.affiliation: Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain.
authors.forename: M V
authors.initials: MV
authors.lastname: Mateos
authors.affiliation: Hospital 12 de Octubre, Madrid, Spain.
authors.forename: J J
authors.initials: JJ
authors.lastname: Lahuerta
authors.affiliation: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA, Pamplona, Spain.
authors.forename: J F
authors.initials: JF
authors.lastname: San-Miguel
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D015415:Biomarkers; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002453:Cell Cycle; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling; D018740:Genetic Heterogeneity; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D009154:Mutation; D060787:Neoplasm Grading; D010641:Phenotype; D010950:Plasma Cells / Q000378:metabolism* / Q000473:pathology*; D011379:Prognosis; D059010:Single-Cell Analysis; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D015415:Biomarkers