title: Clinical drug resistance linked to interconvertible phenotypic and functional states of tumor-propagating cells in multiple myeloma.
abstract: The phenotype and function of cells enriched in tumor-propagating activity and their relationship to the phenotypic architecture in multiple myeloma (MM) are controversial. Here, in a cohort of 30 patients, we show that MM composes 4 hierarchically organized, clonally related subpopulations, which, although phenotypically distinct, share the same oncogenic chromosomal abnormalities as well as immunoglobulin heavy chain complementarity region 3 area sequence. Assessed in xenograft assays, myeloma-propagating activity is the exclusive property of a population characterized by its ability for bidirectional transition between the dominant CD19(-)CD138(+) plasma cell (PC) and a low frequency CD19(-)CD138(-) subpopulation (termed Pre-PC); in addition, Pre-PCs are more quiescent and unlike PCs, are primarily localized at extramedullary sites. As shown by gene expression profiling, compared with PCs, Pre-PCs are enriched in epigenetic regulators, suggesting that epigenetic plasticity underpins the phenotypic diversification of myeloma-propagating cells. Prospective assessment in paired, pretreatment, and posttreatment bone marrow samples shows that Pre-PCs are up to 300-fold more drug-resistant than PCs. Thus, clinical drug resistance in MM is linked to reversible, bidirectional phenotypic transition of myeloma-propagating cells. These novel biologic insights have important clinical implications in relation to assessment of minimal residual disease and development of alternative therapeutic strategies in MM.
authors.affiliation: Centre for Haematology, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Aristeidis
authors.initials: A
authors.lastname: Chaidos
authors.forename: Chris P
authors.initials: CP
authors.lastname: Barnes
authors.forename: Gillian
authors.initials: G
authors.lastname: Cowan
authors.forename: Philippa C
authors.initials: PC
authors.lastname: May
authors.forename: Valeria
authors.initials: V
authors.lastname: Melo
authors.forename: Evdoxia
authors.initials: E
authors.lastname: Hatjiharissi
authors.forename: Maria
authors.initials: M
authors.lastname: Papaioannou
authors.forename: Heather
authors.initials: H
authors.lastname: Harrington
authors.forename: Helen
authors.initials: H
authors.lastname: Doolittle
authors.forename: Evangelos
authors.initials: E
authors.lastname: Terpos
authors.forename: Meletios
authors.initials: M
authors.lastname: Dimopoulos
authors.forename: Saad
authors.initials: S
authors.lastname: Abdalla
authors.forename: Helen
authors.initials: H
authors.lastname: Yarranton
authors.forename: Kikkeri
authors.initials: K
authors.lastname: Naresh
authors.forename: Letizia
authors.initials: L
authors.lastname: Foroni
authors.forename: Alistair
authors.initials: A
authors.lastname: Reid
authors.forename: Amin
authors.initials: A
authors.lastname: Rahemtulla
authors.forename: Michael
authors.initials: M
authors.lastname: Stumpf
authors.forename: Irene
authors.initials: I
authors.lastname: Roberts
authors.forename: Anastasios
authors.initials: A
authors.lastname: Karadimitris
mesh_terms: D000818:Animals; D002469:Cell Separation; D019008:Drug Resistance, Neoplasm / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008962:Models, Theoretical; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome; D014183:Transplantation, Heterologous