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.
Highlights
Chronic myeloid leukemia (CML) is a disease defined by the presence of the BCR-ABL fusion protein, a constitutively active kinase produced by the 9,22 translocation which is sufficient to transform hematopoietic cells [1]
We determined if SB939 would correct BIM splicing and overcome tyrosine kinase inhibitors (TKIs) resistance in CML cell lines with the BIM deletion polymorphism
We have previously shown that CML cells with the BIM deletion polymorphism were more resistant to imatinib when compared to their wildtype counterpart [5]
Summary
Chronic myeloid leukemia (CML) is a disease defined by the presence of the BCR-ABL fusion protein, a constitutively active kinase produced by the 9,22 translocation which is sufficient to transform hematopoietic cells [1]. ABL-specific tyrosine kinase inhibitors (TKIs), such as imatinib mesylate (IM), have significantly improved CML treatment, and prevent transformation to the deadly blast phase of the disease [2, 3]. Patients with suboptimal TKI responses are at risk of developing TKI-resistance and progressing to blast phase [4]. We previously described a germline intronic deletion polymorphism in the BCL2-like 11 (BIM) gene that was sufficient to mediate TKI resistance in CML [5]. In cells which harbor the BIM deletion polymorphism, splicing of BIM pre-mRNA is biased toward the inclusion of exon 3 (E3).
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