Abstract
p15INK4B, a cyclin-dependent kinase inhibitor, has been recognized as a tumor suppressor. Loss of or methylation of the p15INK4B gene in chronic myeloid leukemia (CML) cells enhances myeloid progenitor formation from common myeloid progenitors. Therefore, we examined the effects of overexpressed p15INK4B on proliferation and apoptosis of CML cells. Overexpression of p15INK4B inhibited the growth of K562 cells by downregulation of cyclin-dependent kinase 4 (CDK4) and cyclin D1 expression. Overexpression of p15INK4B also induced apoptosis of K562 cells by upregulating Bax expression and downregulating Bcl-2 expression. Overexpression of p15INK4B together with STI571 (imatinib) or BCR-ABL1 small interfering RNA (siRNA) also enhanced growth inhibition and apoptosis induction of K562 cells. The enhanced effect was also mediated by reduction of cyclin D1 and CDK4 and regulation of Bax and Bcl-2. In conclusion, our study may provide new insights into the role of p15INK4B in CML and a potential therapeutic target for overcoming tyrosine kinase inhibitor resistance in CML.
Highlights
Chronic myeloid leukemia (CML) is a myeloproliferative disease originating from a constitutively active tyrosine kinase, BCR-ABL1 [1]
P15INK4B overexpression increased the apoptosis rate of K562 cells compared with vector, there was no significant difference between the control and vector groups
When the cells with overexpressed p15INK4B were treated with BCR-ABL1 small interfering RNA (siRNA) or STI571, apoptosis rates were further increased compared with BCR-ABL1 siRNA or STI571 alone (P,0.01)
Summary
Chronic myeloid leukemia (CML) is a myeloproliferative disease originating from a constitutively active tyrosine kinase, BCR-ABL1 [1]. Inhibition of BCR-ABL1 with tyrosine kinase inhibitors (TKIs) or small interfering RNA (siRNA) has been demonstrated to be an efficient targeted therapy for CML in the chronic phase [2,3,4,5]. The BCR-ABL1 tyrosine kinase inhibitor, STI571, called imatinib, is widely used in the treatment of CML [6,7]. Exposure of K562 cells to morpholino oligo antisense targeted against BCR-ABL1 inhibited proliferation of K562 cells but did not induce apoptosis [3]. TKIs and targeting of the BCR-ABL1 fusion gene by siRNA have displayed unprecedented efficacy for the treatment of CML [8], there are many shortcomings that limit the application of these therapeutic methods, such as transfection efficiency, toxicity, and drug resistance [9,10]. Second-generation TKIs such as AMN107 appear to be able to improve the treatment of CML, TKI resistance and relapse occur frequently in patients [12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Brazilian Journal of Medical and Biological Research
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
