Differentiation stage of myeloma plasma cells: biological and clinical significance

Data de publicació: 01/02/2017

Autors de IIS La Fe

Lourdes Cordón Gallego

Autor

Autors aliens a IIS La Fe

Paiva B
Puig N
Cedena MT
de Jong BG
Ruiz Y
Rapado I
Martinez-Lopez J
Alignani D
Delgado JA
van Zelm MC
Van Dongen JJ
Pascual M
Agirre X
Prosper F
Martín-Subero JI
Vidriales MB
Gutierrez NC
Hernandez MT
Oriol A
Echeveste MA
Gonzalez Y
Johnson SK
Epstein J
Barlogie B
Morgan GJ
Orfao A
Blade J
Mateos MV
Lahuerta JJ
San-Miguel JF

Grups d'Investigació

Hematología y Hemoterapia

Investigador Principal

Javier De La Rubia Comos

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.

Dades de la publicació

ISSN/ISSNe:: 0887-6924, 1476-5551
Tipus:: Article
Pàgines:: 382-392
DOI:: 10.1038/leu.2016.211
PubMed:: 27479184
Factor d'Impacte:: 5,131 SCImago ℠
Quartil:: Q1 SCImago ℠

Documents

No hi ha documents

Mètriques

Filiacions

Paiva B:: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA, Pamplona, Spain
Puig N:: Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain
Cedena MT:: Hospital 12 de Octubre, Madrid, Spain
de Jong BG:: Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
Ruiz Y:: Hospital 12 de Octubre, Madrid, Spain
Rapado I:: Hospital 12 de Octubre, Madrid, Spain
Martinez-Lopez J:: Hospital 12 de Octubre, Madrid, Spain
Cordon L:: Hospital Universitario y Politécnico La Fe, Valencia, Spain
Alignani D:: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA, Pamplona, Spain
Delgado JA:: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA, Pamplona, Spain
van Zelm MC:: Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

Department of Immunology and Pathology, Monash University, Melbourne VIC Australia
Van Dongen JJ:: Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
Pascual M:: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA, Pamplona, Spain
Agirre X:: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA, Pamplona, Spain
Prosper F:: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA, Pamplona, Spain
Martín-Subero JI:: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Vidriales MB:: Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain
Gutierrez NC:: Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain
Hernandez MT:: Hospital Universitario de Canarias, Tenerife, Spain
Oriol A:: Institut Català d'Oncologia, Institut Josep Carreras, Hospital Germans Trias I Pujol, Badalona, Spain
Echeveste MA:: Hospital de Donostia, San Sebastian, Spain
Gonzalez Y:: Hospital Universitario Josep Trueta, Girona, Spain
Johnson SK:: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Epstein J:: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Barlogie B:: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Morgan GJ:: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Orfao A:: Servicio General de Citometría, Centro de Investigación del Cancer (IBMCC-USAL, CSIC), IBSAL and Department of Medicine, Universidad de Salamanca, Salamanca, Spain
Blade J:: Hospital Clínic, IDIBAPS, Barcelona, Spain
Mateos MV:: Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain
Lahuerta JJ:: Hospital 12 de Octubre, Madrid, Spain
San-Miguel JF:: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA, Pamplona, Spain