title: The HDAC inhibitor SB939 overcomes resistance to BCR-ABL kinase Inhibitors conferred by the BIM deletion polymorphism in chronic myeloid leukemia.
abstract: Chronic 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 deletion-associated TKI resistance.
authors.affiliation: Cancer and Stem Cell Biology Signature Research Programme, Duke-NUS Medical School, Singapore.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Rauzan
authors.affiliation: Cancer and Stem Cell Biology Signature Research Programme, Duke-NUS Medical School, Singapore.|Department of Haematology, Singapore General Hospital, Singapore.
authors.forename: Charles T H
authors.initials: CT
authors.lastname: Chuah
authors.affiliation: Cancer and Stem Cell Biology Signature Research Programme, Duke-NUS Medical School, Singapore.
authors.forename: Tun Kiat
authors.initials: TK
authors.lastname: Ko
authors.affiliation: Cancer and Stem Cell Biology Signature Research Programme, Duke-NUS Medical School, Singapore.|Department of Haematology, Singapore General Hospital, Singapore.|Department of Medical Oncology, National Cancer Centre Singapore, Singapore.|Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: S Tiong
authors.initials: ST
authors.lastname: Ong
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics*; D001562:Benzimidazoles / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D017353:Gene Deletion; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000473:pathology; D012326:RNA Splicing
chemical_list: D000970:Antineoplastic Agents; D000072224:Bcl-2-Like Protein 11; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; C557525:SB939 compound; D016044:Fusion Proteins, bcr-abl