Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The abundance of the BCR/ABL protein critically contributes to CML pathogenesis and drug resistance. However, understanding of molecular mechanisms underlying BCR/ABL gene regulation remains incomplete. While BCR/ABL kinase inhibitors have shown unprecedented efficacy in the clinic, most patients relapse. In this study, we demonstrated that the Sp1 oncogene functions as a positive regulator for BCR/ABL expression. Inactivation of Sp1 by genetic and pharmacological approaches abrogated BCR/ABL expression, leading to suppression of BCR/ABL kinase signaling and CML cell proliferation. Because of potential adverse side effects of bortezomib (BORT) in imatinib-refractory CML patients, we designed a transferrin (Tf)-targeted liposomal formulation (Tf-L-BORT) for BORT delivery. Cellular uptake assays showed that BORT was efficiently delivered into K562 cells, with the highest efficacy obtained in Tf-targeted group. After administered into mice, L-BORT exhibited slower clearance with less toxicity compared to free BORT. Furthermore, L-BORT exposure significantly blocked BCR/ABL kinase activities and sensitized CML cell lines, tumor cells and doxorubicin (DOX) resistant cells to DOX. This occurred through the more pronounced inhibition of BCR/ABL activity by L-BORT and DOX. Collectively, these findings highlight the therapeutic relevance of disrupting BCR/ABL protein expression and strongly support the utilization of L-BORT alone or in combination with DOX to treat CML patients with overexpressing BCR/ABL.
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PMID:Liposomal bortezomib is active against chronic myeloid leukemia by disrupting the Sp1-BCR/ABL axis. 2714 31

Background: The development of drug resistance and the persistence of leukemia stem cells are major obstacles for the use of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML). The induction of autophagic death in tumor cells represents a new route for leukemia treatment. Our previous study showed that infection of CML cells with oncolytic viruses carrying the autophagy gene Beclin1 downregulated BCR/ABL protein expression and significantly increased the killing effect of the oncolytic viruses on CML cells via autophagy activation. However, the specific molecular mechanisms underlying the regulation of BCR/ABL and Beclin1-dependent CML cell killing remain unclear. Methods: A physical interaction between BCR/ABL and Beclin1 was characterized via GST-pulldown, co-IP and dual-luciferase reporter assays. Cell proliferation was examined via CCK-8 and clone formation assays. The expression levels of the related proteins were measured via Western blotting. Autophagosomes were observed under transmission electron microscopy. Lentiviral vectors carrying Atg7/UVRAG shRNA or the Beclin1 gene were used to modulate the expression levels of the indicated genes. Immunofluorescence were performed to examine colocalization of BCR/ABL and p62/SQSTM1. CD34+CD38- cells were isolated from bone marrow samples from CML patients via fluorescence-activated cell sorting. Results: In this study, we observed that Beclin1 directly interacts with BCR/ABL. Beclin1 inhibited the activity of the BCR/ABL promoter to downregulate the level of BCR/ABL protein and to promote the downstream colocalization of p62/SQSTM1 and BCR/ABL to autolysosomes for degradation via activation of the autophagy signaling pathway. In CML cell lines, primary cells and CD34+CD38- leukemia stem cells, Beclin1 overexpression significantly inhibited cell growth and proliferation and induced autophagy. Conclusion: Taken together, our results suggest that autophagy induction via Beclin1 overexpression might offer new approaches for treating TKI-resistant CML and for promoting the clearance of leukemia stem cells, both of which have important clinical implications.
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PMID:The molecular mechanisms underlying BCR/ABL degradation in chronic myeloid leukemia cells promoted by Beclin1-mediated autophagy. 3123 74


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