title: The myeloma stem cell concept, revisited: from phenomenology to operational terms.
abstract: The concept of the myeloma stem cell may have important therapeutic implications, yet its demonstration has been hampered by a lack of consistency in terms and definitions. Here, we summarize the current documentation and propose single-cell in vitro studies for future translational studies. By the classical approach, a CD19-/CD45low/-/CD38high/CD138+malignant plasma cell, but not the CD19+/CD38low/-memory B cell compartment, is enriched for tumorigenic cells that initiate myeloma in xenografted immunodeficient mice, supporting that myeloma stem cells are present in the malignant PC compartment. Using a new approach, analysis of c-DNA libraries from CD19+/CD27+/CD38-single cells has identified clonotypic memory B cell, suggested to be the cell of origin. This is consistent with multiple myeloma being a multistep hierarchical process before or during clinical presentation. We anticipate that further characterization will require single cell geno- and phenotyping combined with clonogenic assays. To implement such technologies, we propose a revision of the concept of a myeloma stem cell by including operational in vitro assays to describe the cellular components of origin, initiation, maintenance, and evolution of multiple myeloma. These terms are in accordance with recent (2012) consensus statements on the definitions, assays, and nomenclature of cancer stem cells, which is technically precise without completely abolishing established terminology. We expect that this operational model will be useful for future reporting of parameters used to identify and characterize the multiple myeloma stem cells. We strongly recommend that these parameters include validated standard technologies, reproducible assays, and, most importantly, supervised prospective sampling of selected biomaterial which reflects clinical stages, disease spectrum, and therapeutic outcome. This framework is key to the characterization of the cellular architecture of multiple myeloma and its use in precision medicine.
authors.affiliation: Department of Haematology Aalborg University Hospital, Denmark haej@rn.dk.|Clinical Cancer Research Center, Aalborg University Hospital, Denmark.|The Department of Clinical Medicine, Aalborg University, Denmark.
authors.forename: Hans Erik
authors.initials: HE
authors.lastname: Johnsen
authors.affiliation: Department of Haematology Aalborg University Hospital, Denmark.|Clinical Cancer Research Center, Aalborg University Hospital, Denmark.|The Department of Clinical Medicine, Aalborg University, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Bøgsted
authors.affiliation: Department of Haematology Aalborg University Hospital, Denmark.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmitz
authors.affiliation: Department of Haematology Aalborg University Hospital, Denmark.
authors.forename: Julie Støve
authors.initials: JS
authors.lastname: Bødker
authors.affiliation: Department of Haematology Aalborg University Hospital, Denmark.|Clinical Cancer Research Center, Aalborg University Hospital, Denmark.|The Department of Clinical Medicine, Aalborg University, Denmark.
authors.forename: Tarec Christoffer
authors.initials: TC
authors.lastname: El-Galaly
authors.affiliation: Department of Hematopathology, Aalborg University Hospital, Denmark.
authors.forename: Preben
authors.initials: P
authors.lastname: Johansen
authors.affiliation: The Department of Internal Medicine I, Division of Hematology Medical University of Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
authors.affiliation: Wilhelminen Cancer Research Institute and Ludwig Boltzmann Cluster Oncology, First Department of Medicine, Center for Oncology and Hematology, Vienna, Austria.
authors.forename: Niklas
authors.initials: N
authors.lastname: Zojer
authors.affiliation: Department of Hematology and Immunology-Myeloma Center, Vrije University Brussels, Belgium.
authors.forename: Els
authors.initials: E
authors.lastname: Van Valckenborgh
authors.affiliation: Department of Hematology and Immunology-Myeloma Center, Vrije University Brussels, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Vanderkerken
authors.affiliation: Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: van Duin
authors.affiliation: Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Sonneveld
authors.affiliation: Department of Medicine and Cytometry Service (NUCLEUS), Cancer Research Center (IBMCC, USAL-CSIC), Institute for Biomedical Research of Salamanca (IBSAL), University of Salamanca (USAL), Spain.
authors.forename: Martin
authors.initials: M
authors.lastname: Perez-Andres
authors.affiliation: Department of Medicine and Cytometry Service (NUCLEUS), Cancer Research Center (IBMCC, USAL-CSIC), Institute for Biomedical Research of Salamanca (IBSAL), University of Salamanca (USAL), Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Orfao
authors.affiliation: Department of Haematology Aalborg University Hospital, Denmark.|Clinical Cancer Research Center, Aalborg University Hospital, Denmark.|The Department of Clinical Medicine, Aalborg University, Denmark.
authors.forename: Karen
authors.initials: K
authors.lastname: Dybkær
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers; D000066670:Cell Plasticity; D000066673:Cell Self Renewal; D019008:Drug Resistance, Neoplasm; D014644:Genetic Variation; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers