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

Chronic myelogenous leukemia (CML) is characterized by the expression of the BCR-ABL tyrosine kinase, which results in increased cell proliferation and inhibition of apoptosis. In this study, we show in both BCR-ABL cells (Mo7e-p210 and BaF/3-p210) and primary CML CD34+ cells that STI571 inhibition of BCR-ABL tyrosine kinase activity results in a G(1) cell cycle arrest mediated by the PI3K pathway. This arrest is associated with a nuclear accumulation of p27(Kip1) and down-regulation of cyclins D and E. As a result, there is a reduction of the cyclin E/Cdk2 kinase activity and of the retinoblastoma protein phosphorylation. By quantitative reverse transcription-PCR we show that BCR-ABL/PI3K regulates the expression of p27(Kip1) at the level of transcription. We further show that BCR-ABL also regulates p27(Kip1) protein levels by increasing its degradation by the proteasome. This degradation depends on the ubiquitinylation of p27(Kip1) by Skp2-containing SFC complexes: silencing the expression of Skp2 with a small interfering RNA results in the accumulation of p27(Kip1). We also demonstrate that BCR-ABL cells show transcriptional up-regulation of Skp2. Finally, expression of a p27(Kip1) mutant unable of being recognized by Skp2 results in inhibition of proliferation of BCR-ABL cells, indicating that the degradation of p27(Kip1) contributes to the pathogenesis of CML. In conclusion, these results suggest that BCR-ABL regulates cell cycle in CML cells at least in part by inducing proteasome-mediated degradation of the cell cycle inhibitor p27(Kip1) and provide a rationale for the use of inhibitors of the proteasome in patients with BCR-ABL leukemias.
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PMID:BCR-ABL induces the expression of Skp2 through the PI3K pathway to promote p27Kip1 degradation and proliferation of chronic myelogenous leukemia cells. 1583 59

Our previous study demonstrates that Bcr-Abl fusion oncogene frequently found in chronic myeloid leukemia (CML) cells can up-regulate Skp2 expression via transcriptional activation. However, Bcr-Abl also modulates Skp2 protein stability in these cells. Treatment of Bcr-Abl kinase inhibitor imatinib led to G1 growth arrest accompanied with reduced Skp2 expression. Interestingly, reduction of Skp2 protein occurred prior to down-regulation of Skp2 mRNA suggesting a post-translational control. The half-life of Skp2 protein was significantly attenuated in imatinib-treated cells. These effects are not cell line specific because similar results were also found in CML cells obtained from patients. Knockdown of Bcr-Abl similarly caused Skp2 protein instability. The decrease of Skp2 was induced by increased protein degradation through the ubiquitin/proteasome pathway. Imatinib treatment or Bcr-Abl knockdown reduced Emi1, an endogenous inhibitor of the E3 ligase APC/Cdh1 which mediated Skp2 degradation. We found that Emi1 stability was regulated by phosphorylation and mutation of tyrosine 142 reduced the stability. Our data suggested Bcr-Abl-induced Emi1 phosphorylation might be mediated by Src kinase. Firstly, Src inhibitor SU6656 inhibited Emi1 tyrosine phosphorylation in K562 cells. Secondly, transfection of v-Src rescued the reduction of Emi1 by imatinib. Thirdly, mutation of tyrosine 142 to phenylalanine (Y142F) abolished the phosphorylation of Emi1 by recombinant Src kinase. In addition, ectopic expression of wild type but not Y142F mutant Emi1 counteracted imatinib-caused growth arrest. Collectively, our results suggest that Bcr-Abl increases Emi1 phosphorylation and stability to prevent Skp2 protein degradation via APC/Cdh1-induced ubiquitination and to enhance proliferation of CML cells.
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PMID:Bcr-Abl-induced tyrosine phosphorylation of Emi1 to stabilize Skp2 protein via inhibition of ubiquitination in chronic myeloid leukemia cells. 2071 63

Anaphase promoting complex cofactor Cdh1 plays a critical role in tumor suppression and genomic stability in cancer. However, its role in chronic myeloid leukemia (CML) remains unclear. We treated both wild-type and imatinib-resistant K562 cells with imatinib or nilotinib and bortezomib, respectively. The siRNAs of Cdh1 and Skp2 were designed and transiently transfected with HiPerFect transfection reagent into CML cells. Expression of Cdh1-Skp2-p27 pathway proteins were detected by Western blotting. Cell cycle, cell apoptosis and cellular morphology were detected by flow cytometry and Wright staining. Our study revealed that Cdh1 was expressed at lower levels in imatinib-resistant CML blast crisis (BC) patients than imatinib-sensitive ones. Moreover, imatinib and bortezomib induced cell cycle quiescence or arrest, upregulation and nuclear relocation of Cdh1 in CML cells. Furthermore, nilotinib and bortezomib resulted in upregulation of Cdh1 in imatinib-resistant CML cells. Conversely, Cdh1 silencing resulted in stabilization of Skp2 and Cdc20, subsequently promoting G1-S transition and formation of multinucleated cells. Our study shows that TKIs and bortezomib can regulate the cell cycle and cell apoptosis via regulation of the expression and redistribution of Cdh1 in CML-BC, which sheds light on the orchestration of crosstalk between TKIs and bortezomib in imatinib-resistant CML-BC. Additionally, Cdh1 tends to play an important role in maintenance of genomic stability, the detailed mechanisms deserve further study.
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PMID:Imatinib and bortezomib induce the expression and distribution of anaphase-promoting complex adaptor protein Cdh1 in blast crisis of chronic myeloid leukemia. 2200 44

Although 1,2,3,4,6-penta-O-galloyl-beta-d-glucose (PGG) was well known to have antitumor activities in breast, prostate, kidney, liver cancers and HL-60 leukemia via regulation of caspase 3, p53, S-phase kinase-associated protein 2 (Skp2) and insulin receptor signaling, the underlying mechanism of PGG-induced apoptosis linked with reactive oxygen species (ROS) mediated c-Jun N-terminal kinase (JNK) and DAXX was never elucidated in chronic myeloid leukemia (CML) K562 cells until now. Herein PGG significantly decreased the viability of CML cell lines such as K562 and KBM-5 without hurting normal peripheral blood lymphocytes (PBLs). PGG increased the number of TUNEL-positive cells and the sub-G1 cell population as well as activated caspase cascades including caspase-8, -9 and -3 in K562 cells. Interestingly, a significant activation of JNK by PGG was observed by MULTIPLEX assay and Western blotting. Conversely, JNK inhibitor D-JNKi suppressed the cleavages of caspase 3 and PARP induced by PGG in K562 cells. Also, PGG dramatically enhanced generation of ROS and reduced the expression of death-domain-associated protein (DAXX). Of note, ROS inhibitor acetyl-L-cysteine (NAC) reversed JNK-dependent apoptosis and DAXX inhibition induced by PGG. Overall, these findings suggest that ROS-dependent JNK activation and DAXX downregulation are critically involved in PGG-induced apoptosis in K562 cells.
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PMID:Reactive oxygen species-mediated activation of JNK and down-regulation of DAXX are critically involved in penta-O-galloyl-beta-d-glucose-induced apoptosis in chronic myeloid leukemia K562 cells. 2277 29

Cyclin-dependent kinase subunit 1 (Cks1) is a critical rate-limiting component of the Skp1-Cullin1-Skp2 (SCF(Skp2)) ubiquitin ligase that controls cell cycle inhibitor abundance. Cyclin-dependent kinase (Cdk) inhibitors (CKIs) regulate hematopoietic stem cell (HSC) self-renewal, regeneration after cytotoxic stress and tumor cell proliferation. We thus studied the role of Cks1 in HSC and in a prototypic stem cell disorder, chronic myeloid leukemia (CML). Cks1 transcript was highly expressed in Lin-Sca-1+Kit+ (LSK) HSC, and the loss resulted in accumulation of the SCF(Skp2)/Cks1 substrates p21, p27, p57 and p130 particularly in CD150+ LSK cells. This accumulation correlated with decreased proliferation and accumulation of Cks1(-/-) HSC, slower regeneration after stress and prolonged HSC quiescence. At the hematopoietic progenitor (HPC) level, loss of Cks1 sensitized towards apoptosis. In CML, Cks1 expression was increased, and treatment with the Abl kinase inhibitor, imatinib, reduced Cks1 expression. Also, we found that Cks1 is critical for Bcr-Abl-induced cytokine-independent clonogenic activity. In conclusion, our study presents a novel function of Cks1 in maintaining HSC/HPC homeostasis and shows that Cks1 is a possible target in therapies aimed at the SCF(Skp2)/Cks1 complex that controls CKI abundance and cancer cell proliferation.
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PMID:Cks1 is a critical regulator of hematopoietic stem cell quiescence and cycling, operating upstream of Cdk inhibitors. 2541 5

Constitutive activation of tyrosine kinase Bcr-Abl is the leading cause of the development and progression of chronic myeloid leukemia (CML). Currently, the application of tyrosine kinase inhibitors (TKIs) targeting the Bcr-Abl is the primary therapy for CML patients. However, acquired resistance to TKIs that develops overtime in the long-term administration renders TKIs ineffective to patients with advanced CML. Therefore, increasing studies focus on the amplified expression or activation of Bcr-Abl which is proposed to contribute to the advanced phase. Here, we show that S-phase kinase-associated protein 2 (SKP2) acts as a co-regulator of Bcr-Abl by mediating its K63-linked ubiquitination and activation. Further investigations show that USP10 as a novel deubiquitinase of SKP2 amplifies the activation of Bcr-Abl via mediating deubiquitination and stabilization of SKP2 in CML cells. Moreover, inhibition of USP10 significantly suppresses the proliferation of both imatinib-sensitive and imatinib-resistant CML cells, which likely depends on SKP2 status. This findings are confirmed in primary CML cells because these cells are over-expressed with USP10 and SKP2 and are sensitive to a USP10 inhibitor. Taken together, the present study not only provides a novel insight into the amplified activation of Bcr-Abl in CML, but also demonstrates that targeting the USP10/SKP2/Bcr-Abl axis is a potential strategy to overcome imatinib resistance in CML patients.
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PMID:USP10 modulates the SKP2/Bcr-Abl axis via stabilizing SKP2 in chronic myeloid leukemia. 3104 85