Rauzan Muhammad, Chuah Charles T H, Ko Tun Kiat, Ong S Tiong
Cancer and Stem Cell Biology Signature Research Programme, Duke-NUS Medical School, Singapore.
Department of Haematology, Singapore General Hospital, Singapore.
PLoS One. 2017 Mar 16;12(3):e0174107. doi: 10.1371/journal.pone.0174107. eCollection 2017.
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.
慢性粒细胞白血病（CML）的治疗因酪氨酸激酶抑制剂（TKIs）如甲磺酸伊马替尼（IM）而得到改善，但多种因素可导致CML患者出现TKI耐药。导致TKI耐药的一个因素是BCL2样11（BIM）基因中的种系内含子缺失多态性，它会损害BIM促凋亡剪接异构体的表达。SB939（普拉西诺司他）是一种基于异羟肟酸的HDAC抑制剂，具有良好的药代动力学、物理化学和药学性质，我们研究了这种药物是否能克服BIM缺失多态性诱导的TKI耐药。我们发现SB939可纠正具有BIM缺失多态性的CML细胞中的BIM前体mRNA剪接，并在具有BIM缺失多态性的CML细胞系和原代细胞中诱导凋亡性细胞死亡。更重要的是，SB939既能降低具有BIM缺失的CML细胞系和原发性CML祖细胞的活力，又能恢复TKI敏感性。我们的结果表明，SB939克服了BIM缺失多态性诱导的TKI耐药，并提示SB939可能对治疗具有BIM缺失相关TKI耐药的CML患者有用。
