Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0174107
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dc.titleThe HDAC inhibitor SB939 overcomes resistance to BCR-ABL kinase Inhibitors conferred by the BIM deletion polymorphism in chronic myeloid leukemia
dc.contributor.authorRauzan M.
dc.contributor.authorChuah C.T.H.
dc.contributor.authorKo T.K.
dc.contributor.authorTiong Ong S.
dc.date.accessioned2020-03-27T06:26:59Z
dc.date.available2020-03-27T06:26:59Z
dc.date.issued2017
dc.identifier.citationRauzan M., Chuah C.T.H., Ko T.K., Tiong Ong S. (2017). The HDAC inhibitor SB939 overcomes resistance to BCR-ABL kinase Inhibitors conferred by the BIM deletion polymorphism in chronic myeloid leukemia. PLoS ONE 12 (3) : e0174107. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0174107
dc.identifier.issn19326203
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/166015
dc.description.abstractChronic myeloid leukemia (CML) treatment has been improved by tyrosine kinase inhibitors (TKIs) such as imatinib mesylate (IM) but various factors can cause TKI resistance in patients with CML. One factor which contributes to TKI resistance is a germline intronic deletion polymorphism in the BCL2-like 11 (BIM) gene which impairs the expression of pro-apoptotic splice isoforms of BIM. SB939 (pracinostat) is a hydroxamic acid based HDAC inhibitor with favorable pharmacokinetic, physicochemical and pharmaceutical properties, and we investigated if this drug could overcome BIM deletion polymorphism-induced TKI resistance. We found that SB939 corrects BIM pre-mRNA splicing in CML cells with the BIM deletion polymorphism, and induces apoptotic cell death in CML cell lines and primary cells with the BIM deletion polymorphism. More importantly, SB939 both decreases the viability of CML cell lines and primary CML progenitors with the BIM deletion and restores TKI-sensitivity. Our results demonstrate that SB939 overcomes BIM deletion polymorphism-induced TKI resistance, and suggest that SB939 may be useful in treating CML patients with BIM deletionassociated TKI resistance. © 2017 Rauzan et al.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 author and source are credited.
dc.publisherPublic Library of Science
dc.sourceUnpaywall 20200320
dc.subjectBCR ABL protein
dc.subjectBIM protein
dc.subjectimatinib
dc.subjectpracinostat
dc.subjectprotein tyrosine kinase inhibitor
dc.subjectantineoplastic agent
dc.subjectBCR ABL protein
dc.subjectbenzimidazole derivative
dc.subjectBIM protein
dc.subjectenzyme inhibitor
dc.subjecthistone deacetylase inhibitor
dc.subjectSB939 compound
dc.subjectapoptosis
dc.subjectArticle
dc.subjectBIM gene
dc.subjectcancer resistance
dc.subjectcell viability
dc.subjectchronic myeloid leukemia
dc.subjectcontrolled study
dc.subjectDNA polymorphism
dc.subjectdrug efficacy
dc.subjectdrug mechanism
dc.subjectdrug sensitivity
dc.subjectgene
dc.subjectgene deletion
dc.subjecthuman
dc.subjecthuman cell
dc.subjectleukemia cell
dc.subjectRNA splicing
dc.subjectantagonists and inhibitors
dc.subjectchronic myeloid leukemia
dc.subjectdrug effects
dc.subjectgene deletion
dc.subjectgenetics
dc.subjectK-562 cell line
dc.subjectpathology
dc.subjectAntineoplastic Agents
dc.subjectApoptosis
dc.subjectBcl-2-Like Protein 11
dc.subjectBenzimidazoles
dc.subjectEnzyme Inhibitors
dc.subjectFusion Proteins, bcr-abl
dc.subjectGene Deletion
dc.subjectHistone Deacetylase Inhibitors
dc.subjectHumans
dc.subjectK562 Cells
dc.subjectLeukemia, Myelogenous, Chronic, BCR-ABL Positive
dc.subjectRNA Splicing
dc.typeArticle
dc.contributor.departmentDUKE-NUS MEDICAL SCHOOL
dc.description.doi10.1371/journal.pone.0174107
dc.description.sourcetitlePLoS ONE
dc.description.volume12
dc.description.issue3
dc.description.pagee0174107
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