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Reference: Chaidos, A, Barnes, CP, Cowan, G et al., (2013). Clinical drug resistance linked to interconvertible phenotypic and functional states of tumor-propagating cells in multiple myeloma. Blood, 121 (2), 318-328.Citable link to this page:

 

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.

Peer Review status:Peer reviewedPublication status:PublishedVersion:Accepted manuscript Funder: Leukaemia and Lymphoma Research   Funder: Leuka   Funder: National Institute of Health Research   Notes:© 2013 by The American Society of Hematology

Bibliographic Details

Publisher: American Society of Hematology

Publisher Website: http://www.hematology.org/

Journal: Bloodsee more from them

Publication Website: http://bloodjournal.org/

Issue Date: 2013-01

pages:318-328Identifiers

Urn: uuid:e4726801-c90b-4df6-a103-d733938f892d

Source identifier: 398364

Eissn: 1528-0020

Doi: https://doi.org/10.1182/blood-2012-06-436220

Issn: 0006-4971 Item Description

Type: Journal article;

Language: eng

Version: Accepted manuscriptKeywords: Animals Humans Mice Multiple Myeloma Transplantation, Heterologous Oligonucleotide Array Sequence Analysis Flow Cytometry Cell Separation In Situ Hybridization, Fluorescence Reverse Transcriptase Polymerase Chain Reaction Immunophenotyping Drug Resistance, Neoplasm Phenotype Models, Theoretical Transcriptome Tiny URL: pubs:398364

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Author: Chaidos, A - - - Barnes, CP - - - Cowan, G - - - May, PC - - - Melo, V - - - Hatjiharissi, E - - - Papaioannou, M - - - Harringto

Source: https://ora.ox.ac.uk/objects/uuid:e4726801-c90b-4df6-a103-d733938f892d



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