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dc.contributor.authorAdomako, A.-
dc.contributor.authorCalvo, V.-
dc.contributor.authorBiran, N.-
dc.contributor.authorOsman, K.-
dc.contributor.authorChari, A.-
dc.contributor.authorPaton, J.-
dc.contributor.authorPaton, A.-
dc.contributor.authorMoore, K.-
dc.contributor.authorSchewe, D.-
dc.contributor.authorAguirre-Ghiso, J.-
dc.identifier.citationBMC Cancer, 2015; 15(1):444-1-444-11-
dc.description.abstractThe mechanisms allowing residual multiple myeloma (MM) cells to persist after bortezomib (Bz) treatment remain unclear. We hypothesized that studying the biology of bortezomib-surviving cells may reveal markers to identify these cells and survival signals to target and kill residual MM cells.We used H2B-GFP label retention, biochemical tools and in vitro and in vivo experiments to characterize growth arrest and the unfolded protein responses in quiescent Bz-surviving cells. We also tested the effect of a demethylating agent, 5-Azacytidine, on Bz-induced quiescence and whether inhibiting the chaperone GRP78/BiP (henceforth GRP78) with a specific toxin induced apoptosis in Bz-surviving cells. Finally, we used MM patient samples to test whether GRP78 levels might associate with disease progression. Statistical analysis employed t-test and Mann-Whitney tests at a 95% confidence.We report that Bz-surviving MM cells in vitro and in vivo enter quiescence characterized by p21(CIP1) upregulation. Bz-surviving MM cells also downregulated CDK6, Ki67 and P-Rb. H2B-GFP label retention showed that Bz-surviving MM cells are either slow-cycling or deeply quiescent. The Bz-induced quiescence was stabilized by low dose (500nM) of 5-azacytidine (Aza) pre-treatment, which also potentiated the initial Bz-induced apoptosis. We also found that expression of GRP78, an unfolded protein response (UPR) survival factor, persisted in MM quiescent cells. Importantly, GRP78 downregulation using a specific SubAB bacterial toxin killed Bz-surviving MM cells. Finally, quantification of Grp78(high)/CD138+ MM cells from patients suggested that high levels correlated with progressive disease.We conclude that Bz-surviving MM cells display a GRP78(HIGH)/p21(HIGH)/CDK6(LOW)/P-Rb(LOW) profile, and these markers may identify quiescent MM cells capable of fueling recurrences. We further conclude that Aza + Bz treatment of MM may represent a novel strategy to delay recurrences by enhancing Bz-induced apoptosis and quiescence stability.-
dc.description.statementofresponsibilityAlfred Adomako, Veronica Calvo, Noa Biran, Keren Osman, Ajai Chari, James C Paton, Adrienne W Paton, Kateri Moore, Denis M Schewe, and Julio A Aguirre-Ghiso-
dc.publisherBioMed Central-
dc.rights© 2015 Adomako et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.-
dc.subjectMultiple Myeloma-
dc.subjectNeoplasm Recurrence, Local-
dc.subjectHeat-Shock Proteins-
dc.subjectXenograft Model Antitumor Assays-
dc.subjectCell Survival-
dc.subjectGene Expression Regulation, Neoplastic-
dc.subjectMiddle Aged-
dc.subjectCyclin-Dependent Kinase 6-
dc.subjectp21-Activated Kinases-
dc.subjectEndoplasmic Reticulum Chaperone BiP-
dc.titleIdentification of markers that functionally define a quiescent multiple myeloma cell sub-population surviving bortezomib treatment-
dc.typeJournal article-
dc.identifier.orcidPaton, J. [0000-0001-9807-5278]-
Appears in Collections:Aurora harvest 7
Molecular and Biomedical Science publications

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