Dataset Information

Contributions of MET activation to BCR-ABL1 tyrosine kinase inhibitor resistance in chronic myeloid leukemia cells.

ABSTRACT: Resistance to the breakpoint cluster region-abelson 1 (BCR-ABL1) tyrosine kinase inhibitor (TKI) imatinib poses a major problem when treating chronic myeloid leukemia (CML). Imatinib resistance often results from a secondary mutation in BCR-ABL1. However, in the absence of a mutation in BCR-ABL1, the basis of BCR-ABL1-independent resistance must be elucidated. To gain insight into the mechanisms of BCR-ABL1-independent imatinib resistance, we performed an array-based comparative genomic hybridization. We identified various resistance-related genes, and focused on MET. Treatment with a MET inhibitor resensitized K562/IR cells to BCR-ABL1 TKIs. Combined treatment of K562/IR cells with imatinib and a MET inhibitor suppressed extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) activation, but did not affect AKT activation. Our findings implicate the MET/ERK and MET/JNK pathways in conferring resistance to imatinib, providing new insights into the mechanisms of BCR-ABL1 TKI resistance in CML.

SUBMITTER: Tsubaki M

PROVIDER: S-EPMC5503566 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Contributions of MET activation to BCR-ABL1 tyrosine kinase inhibitor resistance in chronic myeloid leukemia cells.

Tsubaki Masanobu M Takeda Tomoya T Kino Toshiki T Sakai Kazuko K Itoh Tatsuki T Imano Motohiro M Nakayama Takashi T Nishio Kazuto K Satou Takao T Nishida Shozo S

Oncotarget 20170601 24

Resistance to the breakpoint cluster region-abelson 1 (BCR-ABL1) tyrosine kinase inhibitor (TKI) imatinib poses a major problem when treating chronic myeloid leukemia (CML). Imatinib resistance often results from a secondary mutation in BCR-ABL1. However, in the absence of a mutation in BCR-ABL1, the basis of BCR-ABL1-independent resistance must be elucidated. To gain insight into the mechanisms of BCR-ABL1-independent imatinib resistance, we performed an array-based comparative genomic hybridiz ...[more]

PMID: 28418880

Similar Datasets

Project description:BackgroundIt is difficult for chronic myeloid leukemia (CML) patients with BCR::ABL1 independent drug resistance to achieve optimal efficacy. The aim of this study is to investigate the BCR::ABL1 kinase independent mechanism of tyrosine kinase inhibitor (TKI) resistance in CML patients to develop targeted therapeutic strategy.MethodsHerein, we analyzed the long non-coding RNA (lncRNA) and messenger RNA (mRNA) expression profiles of patients who achieved sustained deep molecular response (DMR) after TKI treatment and patients with non-DMR using RNA-seqencing. Furthermore, the differentially expressed lncRNAs and mRNAs were identified. The expression of chosen lncRNA was validated in an expanded cohort, and bioinformatics analysis was performed to analyze the function of selected mRNA.ResultsLncRNA data analysis indicated the diversity lncRNA profiles among healthy individuals, CML patients with non-DMR, and CML patients with DMR. Differential expression analysis and Veen plot of up-regulated lncRNAs in patients with non-DMR (compared with healthy individuals) and down-regulated lncRNAs in patients with DMR (compared to patients with non-DMR) revealed that lncRNA CBR3-AS1 overexpression might be related to BCR::ABL1 independent TKI resistance of CML patients. The expression of CBR3-AS1 was then verified in an expanded cohort, suggesting that, compared with control group, there was no statistical difference of CBR3-AS1 expression in DMR group, whereas, CBR3-AS1 was up-regulated in non-DMR group. Moreover, the mRNA data analysis of RNA-sequencing was performed. We considered genes that up-regulated in non-DMR group (compared with control group), down-regulated in DMR group (compared with non-DMR group), showed no statistical difference between control and DMR group as the potential genes that associated with TKI resistance of CML patients. A total of 55 corresponding mRNAs were obtained including KCNA6, a target gene of CBR3-AS1. Further bioinformatics analysis showed that the major interacted genes of KCNA6 were enriched in several resistance-associated pathways including interleukin -17 signaling pathway and cyclic adenosine monophosphate signaling pathway.ConclusionsIn conclusion, this work indicates that CBR3-AS1 might be involved in BCR::ABL1 independent TKI resistance of CML patients through targeting KCNA6, providing a novel target for intervention treatment of CML patients with BCR::ABL1 independent TKI resistance.

Project description:Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia in the chronic phase (CML-CP). However, it is unlikely that they can completely "cure" the disease. This might be because some subpopulations of CML-CP cells such as stem and progenitor cells are resistant to chemotherapy, even to the new generation of TKIs. Therefore, it is important to look for new methods of treatment to improve therapeutic outcomes. Previously, we have shown that class I p21-activated serine/threonine kinases (PAKs) remained active in TKI-naive and TKI-treated CML-CP leukemia stem and early progenitor cells. In this study, we aimed to determine if simultaneous inhibition of BCR-ABL1 oncogenic tyrosine kinase and PAK1/2 serine/threonine kinase exert better anti-CML effect than that of individual treatments. PAK1 was inhibited by small-molecule inhibitor IPA-3 (p21-activated kinase inhibitor III), PAK2 was downregulated by specific short hairpin RNA (shRNA), and BCR-ABL1 tyrosine kinase was inhibited by imatinib (IM). The studies were conducted by using (i) primary CML-CP stem/early progenitor cells and normal hematopoietic counterparts isolated from the bone marrow of newly diagnosed patients with CML-CP and from healthy donors, respectively, (ii) CML-blast phase cell lines (K562 and KCL-22), and (iii) from BCR-ABL1-transformed 32Dcl3 cell line. Herein, we show that inhibition of the activity of PAK1 and/or PAK2 enhanced the effect of IM against CML cells without affecting the normal cells. We observed that the combined use of IM with IPA-3 increased the inhibition of growth and apoptosis of leukemia cells. To evaluate the type of interaction between the two drugs, we performed median effect analysis. According to our results, the type and strength of drug interaction depend on the concentration of the drugs tested. Generally, combination of IM with IPA-3 at the 50% of the cell kill level (EC50) generated synergistic effect. Based on our results, we hypothesize that IM, a BCR-ABL1 tyrosine kinase inhibitor, combined with a PAK1/2 inhibitor facilitates eradication of CML-CP cells.

Dataset Information

Contributions of MET activation to BCR-ABL1 tyrosine kinase inhibitor resistance in chronic myeloid leukemia cells.

Publications

Contributions of MET activation to BCR-ABL1 tyrosine kinase inhibitor resistance in chronic myeloid leukemia cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets