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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.

Original publication

DOI

10.1182/blood-2012-06-436220

Type

Journal article

Journal

Blood

Publication Date

10/01/2013

Volume

121

Pages

318 - 328

Keywords

Animals, Cell Separation, Drug Resistance, Neoplasm, Flow Cytometry, Humans, Immunophenotyping, In Situ Hybridization, Fluorescence, Mice, Models, Theoretical, Multiple Myeloma, Oligonucleotide Array Sequence Analysis, Phenotype, Reverse Transcriptase Polymerase Chain Reaction, Transcriptome, Transplantation, Heterologous