title: Phenotypic and genomic analysis of multiple myeloma minimal residual disease tumor cells: a new model to understand chemoresistance.
abstract: Persistence of chemoresistant minimal residual disease (MRD) plasma cells (PCs) is associated with inferior survival in multiple myeloma (MM). Thus, characterization of the minor MRD subclone may represent a unique model to understand chemoresistance, but to our knowledge, the phenotypic and genetic features of the MRD subclone have never been investigated. Here, we compared the antigenic profile of MRD vs diagnostic clonal PCs in 40 elderly MM patients enrolled in the GEM2010MAS65 study and showed that the MRD subclone is enriched in cells overexpressing integrins (CD11a/CD11c/CD29/CD49d/CD49e), chemokine receptors (CXCR4), and adhesion molecules (CD44/CD54). Genetic profiling of MRD vs diagnostic PCs was performed in 12 patients; 3 of them showed identical copy number alterations (CNAs), in another 3 cases, MRD clonal PCs displayed all genetic alterations detected at diagnosis plus additional CNAs that emerged at the MRD stage, whereas in the remaining 6 patients, there were CNAs present at diagnosis that were undetectable in MRD clonal PCs, but also a selected number of genetic alterations that became apparent only at the MRD stage. The MRD subclone showed significant downregulation of genes related to protein processing in endoplasmic reticulum, as well as novel deregulated genes such as ALCAM that is prognostically relevant in MM and may identify chemoresistant PCs in vitro. Altogether, our results suggest that therapy-induced clonal selection could be already present at the MRD stage, where chemoresistant PCs show a singular phenotypic signature that may result from the persistence of clones with different genetic and gene expression profiles. This trial was registered atwww.clinicaltrials.gov as #NCT01237249.
authors.affiliation: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain;
authors.forename: Bruno
authors.initials: B
authors.lastname: Paiva
authors.affiliation: Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca, Centro de Investigación del Cancer, Salamanca, Spain;
authors.forename: Luis A
authors.initials: LA
authors.lastname: Corchete
authors.affiliation: Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca, Centro de Investigación del Cancer, Salamanca, Spain;
authors.forename: Maria-Belen
authors.initials: MB
authors.lastname: Vidriales
authors.affiliation: Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca, Centro de Investigación del Cancer, Salamanca, Spain;
authors.forename: Noemi
authors.initials: N
authors.lastname: Puig
authors.affiliation: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain;
authors.forename: Patricia
authors.initials: P
authors.lastname: Maiso
authors.affiliation: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain;
authors.forename: Idoia
authors.initials: I
authors.lastname: Rodriguez
authors.affiliation: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain;
authors.forename: Diego
authors.initials: D
authors.lastname: Alignani
authors.affiliation: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain;
authors.forename: Leire
authors.initials: L
authors.lastname: Burgos
authors.affiliation: Servicio General de Citometría, Centro de Investigación del Cancer, Instituto de Investigacion Biomedica de Salamanca and Department of Medicine, Universidad de Salamanca, Salamanca, Spain;
authors.forename: Maria-Luz
authors.initials: ML
authors.lastname: Sanchez
authors.affiliation: Servicio General de Citometría, Centro de Investigación del Cancer, Instituto de Investigacion Biomedica de Salamanca and Department of Medicine, Universidad de Salamanca, Salamanca, Spain;
authors.forename: Paloma
authors.initials: P
authors.lastname: Barcena
authors.affiliation: Hospital de Donostia, San Sebastian, Spain;
authors.forename: Maria-Asuncion
authors.initials: MA
authors.lastname: Echeveste
authors.affiliation: Hospital Universitario de Canarias, Tenerife, Spain;
authors.forename: Miguel T
authors.initials: MT
authors.lastname: Hernandez
authors.affiliation: Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca, Centro de Investigación del Cancer, Salamanca, Spain;
authors.forename: Ramón
authors.initials: R
authors.lastname: García-Sanz
authors.affiliation: Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca, Centro de Investigación del Cancer, Salamanca, Spain;
authors.forename: Enrique M
authors.initials: EM
authors.lastname: Ocio
authors.affiliation: Hospital Universitari Germans Trias i Pujol, Badalona, Spain;
authors.forename: Albert
authors.initials: A
authors.lastname: Oriol
authors.affiliation: Hospital Vall de Hebron, Barcelona, Spain;
authors.forename: Mercedes
authors.initials: M
authors.lastname: Gironella
authors.affiliation: Hospital Lozano Blesa, Zaragoza, Spain;
authors.forename: Luis
authors.initials: L
authors.lastname: Palomera
authors.affiliation: Hospital Morales Meseguer, Murcia, Spain;
authors.forename: Felipe
authors.initials: F
authors.lastname: De Arriba
authors.affiliation: Hospital Universitario Josep Trueta, Girona, Spain;
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Gonzalez
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR;
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Johnson
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR;
authors.forename: Joshua
authors.initials: J
authors.lastname: Epstein
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR;
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
authors.affiliation: Hospital 12 de Octubre, Madrid, Spain; and.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Lahuerta
authors.affiliation: Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Blade
authors.affiliation: Servicio General de Citometría, Centro de Investigación del Cancer, Instituto de Investigacion Biomedica de Salamanca and Department of Medicine, Universidad de Salamanca, Salamanca, Spain;
authors.forename: Alberto
authors.initials: A
authors.lastname: Orfao
authors.affiliation: Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca, Centro de Investigación del Cancer, Salamanca, Spain;
authors.forename: María-Victoria
authors.initials: MV
authors.lastname: Mateos
authors.affiliation: Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain;
authors.forename: Jesús F
authors.initials: JF
authors.lastname: San Miguel
mesh_terms: D000368:Aged; D000069286:Bortezomib / Q000008:administration & dosage; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003907:Dexamethasone / Q000008:administration & dosage; D018450:Disease Progression; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D016130:Immunophenotyping; D016023:Integrins / Q000378:metabolism; D000077269:Lenalidomide; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D008957:Models, Genetic; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018365:Neoplasm, Residual / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D010950:Plasma Cells / Q000473:pathology; D011241:Prednisone / Q000008:administration & dosage; D011379:Prognosis; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D015815:Cell Adhesion Molecules; D016023:Integrins; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone; D000077269:Lenalidomide; D008558:Melphalan; D011241:Prednisone