Clinical drug resistance linked to interconvertible phenotypic and functional states of tumor-propagating cells in multiple myeloma

• Published in: Blood 2013-01, Vol.121 (2), p.318-328
• Main Authors: Chaidos, Aristeidis, Barnes, Chris P., Cowan, Gillian, May, Philippa C., Melo, Valeria, Hatjiharissi, Evdoxia, Papaioannou, Maria, Harrington, Heather, Doolittle, Helen, Terpos, Evangelos, Dimopoulos, Meletios, Abdalla, Saad, Yarranton, Helen, Naresh, Kikkeri, Foroni, Letizia, Reid, Alistair, Rahemtulla, Amin, Stumpf, Michael, Roberts, Irene, Karadimitris, Anastasios
• Format: Article
• Language: English
• Subjects: Animals; Cell Separation; Drug Resistance, Neoplasm - immunology; Flow Cytometry; Humans; Immunophenotyping; In Situ Hybridization, Fluorescence; Mice; Models, Theoretical; Multiple Myeloma - immunology; Multiple Myeloma - pathology; Oligonucleotide Array Sequence Analysis; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; Transcriptome; Transplantation, Heterologous
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-06-436220

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. •CD19−CD138+ and CD19−CD138− myeloma cells represent interconvertible phenotypic and functional states and share myeloma-propagating activity.•Nongenetic, including epigenetic, diversification of myeloma-propagating cells is linked to clinical drug resistance.