Clinical studies have shown that the tyrosine kinase inhibitor STI571 effectively controls BCR-ABL-positive chronic myelogenous leukemia (CML). However, disease progression while on STI571 therapy has been reported, suggesting de novo or intrinsic resistance to BCR-ABL-targeted therapy. To investigate possible mediators of acquired STI571 resistance, K562 cells resistant to 5 microM STI571 (K562-R) were cloned and compared to the parental cell population. K562-R cells had reduced BCR-ABL expression and limited activation of BCR-ABL signaling cascades (Stat 5, CrkL, MAPK). STI571 failed to activate caspase cascades or to suppress expression of survival genes (bcl-xL) in resistant cells. Gene sequencing and tyrosine kinase activity measurements demonstrated that K562-R cells retained wild-type and active BCR-ABL tyrosine kinase that was inhibitable by in vitro incubation with STI571, suggesting that BCR-ABL was not coupled to proliferation or survival of K562-R cells. The src-related kinase LYN was highly overexpressed and activated in K562-R cells, and its inhibition reduced proliferation and survival of K562-R cells while having limited effects of K562 cells. Specimens taken from patients with advanced CML that progressed on STI571 therapy also were analyzed for LYN kinase expression, and they were found to be elevated to a level similar to that of K562-R cells. Comparison of samples from patients taken prior to and following STI571 failure suggested that expression and/or activation of LYN/HCK occurs during disease progression. Together, these results suggest that acquired STI571 resistance may be associated with BCR-ABL independence and mediated in part through overexpression of other tyrosine kinases.
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http://dx.doi.org/10.1182/blood.V101.2.690 | DOI Listing |
Gene
January 2024
Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address:
Imatinib is the current gold standard for patients with chronic myeloid leukemia (CML). However, the primary and acquired drug resistance seriously limits the efficacy. To identify novel therapeutic target in Imatinib-resistant CML is of crucial clinical significance.
View Article and Find Full Text PDFCell Death Dis
January 2022
Department of Hematology and Oncology, Shenzhen Children's Hospital, Shenzhen, 518038, China.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with increasing incidence worldwide. Growing evidence suggests that ubiquitin-specific proteases (USPs) play a role in cancer treatment. Dysregulation of miR-146a has been found in both adult and pediatric patients with acute leukemia.
View Article and Find Full Text PDFContext: A portion of patients with chronic myeloid leukaemia (CML) develop resistance to the Bcr-Abl tyrosine kinase inhibitors (TKIs), limiting the clinical applications. Previous results have demonstrated the synergistic effects between cryptotanshinone (CPT) and imatinib on apoptosis of CML cells .
Objective: To determine the antileukemia effects of CPT and TKIs on the resistant CML cells, and further investigate the effect of combined treatment of CPT and imatinib on tumour growth and apoptosis in the xenograft model and clarify its regulatory mechanisms.
Leuk Res
October 2021
School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India. Electronic address:
Background: Drug resistance mechanisms are the regulatory factors associated with drug metabolism and drug transport to inward and outward of the target cells. Maybridge fragment (MBF) library is a collection of pharmacophore rich compounds having affinity with membrane transporters. This study has been designed to evaluate the efficacy of MBFs in overcoming the leukemic cells' resistance to imatinib.
View Article and Find Full Text PDFBioorg Med Chem Lett
July 2021
Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, PR China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang City, Hunan Province 421001, PR China. Electronic address:
The anti-chronic myeloid leukemia activity of thiazole aminobenzamide derivatives in vitro was tested by a methanethiosulfonate (MTS)-based viability assay method, and the result showed that some compounds exhibited good inhibitory activities against human chronic myeloid leukemia cell line K562, imatinib-resistant strain K562/R and T135I mutant cell line BaF-ABL-BCR-T315I. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods were used to analyze the relationship between the structure of thiazole aminobenzamide derivatives and the inhibition of K562/R cell activity. In CoMFA, Q was 0.
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