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Transcriptomics of K562/S and K562/R, KU812/S and KU812/R of imatinib resistant cell using RNA-sequencing.

ABSTRACT: CML-CP Patients showing resistance to Imatinib, due to Bcr-Abl mechanisms of resistance are treated with 2nd and 3rd generation TKIs but some non-responders shown Bcr-Abl independant mechanism of resistance. We hypothesize that this could be due to activation of novel pathway, or activation of downstream molecules of Bcr-Abl pathway. In this study we have performed Transcriptomics and epigenomics analysis of K562 and KU812 CML-BC cell sensitive and resistant to imatinib, ITGB3 showed high transcript levels, and was also hypomethylated in K562/R cells as compared to sensitive counterparts and showed higher protein levels in both K562 and KU812 resistant cell lines. Previous studies in the lab also showed ITGB1 as a differentiator in proteomic analysis and further on-going studies indicate its role in resistance. ITGB1 was however not modulated at transcriptional level. The protein levels of ITGB3 were significantly increased in resistant cells (K562; KU812: while those of ITGB1 were significantly decreased in resistant cells (K562; KU812. With the known switching of integrins, whether higher expression of ITGB3 had a role in modulating the levels of transcriptionally non-regulated ITGB1 was investigated in K562/S cells with ITGB1 knocked down (KD) protein levels of ITGB3 were upregulated as compared to VC. Similarly, knock down of ITGB3 in K562/R resulted in increased level of ITGB1 protein. These striking results confirmed switching of integrins and explained reduced levels of ITGB1 despite no alteration at genomic or transcriptomic level in resistant cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314129 | GEO | 2025/12/25

REPOSITORIES: GEO

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DNA methylation of K562 and KU812 cells sensitive and resistant to imatinib.

Project description:CML-CP Patients showing resistance to Imatinib, due to Bcr-Abl mechanisms of resistance are treated with 2nd and 3rd generation TKIs but some non-responders shown Bcr-Abl independant mechanism of resistance. We hypothesize that this could be due to activation of novel pathway, or activation of downstream molecules of Bcr-Abl pathway. In this study we have performed Transcriptomics and epigenomics analysis of K562 and KU812 CML-BC cell sensitive and resistant to imatinib, ITGB3 showed high transcript levels, and was also hypomethylated in K562/R cells as compared to sensitive counterparts and showed higher protein levels in both K562 and KU812 resistant cell lines. Previous studies in the lab also showed ITGB1 as a differentiator in proteomic analysis and further on-going studies indicate its role in resistance. ITGB1 was however not modulated at transcriptional level. The protein levels of ITGB3 were significantly increased in resistant cells (K562; KU812: while those of ITGB1 were significantly decreased in resistant cells (K562; KU812. With the known switching of integrins, whether higher expression of ITGB3 had a role in modulating the levels of transcriptionally non-regulated ITGB1 was investigated in K562/S cells with ITGB1 knocked down (KD) protein levels of ITGB3 were upregulated as compared to VC. Similarly, knock down of ITGB3 in K562/R resulted in increased level of ITGB1 protein. These striking results confirmed switching of integrins and explained reduced levels of ITGB1 despite no alteration at genomic or transcriptomic level in resistant cells.

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Project description:Tyrosine kinase activity is the crucial enzymatic activity driving all known functions of the BCR-ABL protein and is required for protection from apoptosis by BCR-ABL, therefore, targeting this enzyme is an effective approach for therapeutic strategies. Recently, a novel structural entity, imatinib (STI571; Novartis, Basel, Switzerland), a potent and selective inhibitor of the tyrosine kinase activity of BCR-ABL, has shown promise against Ph-positive leukemia in human clinical trials. However, the emergence of imatinib resistance in patients with acute forms of Ph-positive leukemia has highlighted the need for overriding chemotherapy to eradicate this disease. AMN107 and BMS-354825 are clinically active “next-generation” BCR-ABL inhibitors. One potentially powerful approach is to use these compounds in combination with imatinib. The rationale for such approaches is that an inhibitor cocktail may target the widest range of resistant clones and thereby delay the onset of acquired drug resistance. More potent BCR-ABL inhibitors would be to target residual leukemia that persists in patients in whom imatinib induces durable remission but failed to eradicate the disease. From these points, our studies are performed to determine (1) the differences of molecular signaling pathways between BMS-354825 and imatinib (2) the mechanisms by which drug resistance of BMS-354825 and imatinib occur except for point mutation of BCR-ABL kinase domain. Keywords: drug sensitivity

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Project description:Imatinib is highly effective in the treatment of chronic myelogenous leukemia (CML), but the primary and acquired imatinib resistance remains the big hurdle. Molecular mechanisms for CML resistance to tyrosine kinase inhibitors, beyond point mutations in BCR-ABL kinase domain, still need to be addressed. Here, we demonstrated that TXNIP is a novel BCR-ABL target gene. Suppression of TXNIP is responsible for BCR-ABL triggered glucose metabolic reprogramming and mitochondrial homeostasis. Mechanistically, Miz-1/P300 complex transactivates TXNIP through the recognition of TXNIP core promoter region, responding to the c-Myc suppression by either imatinib or BCR-ABL knockdown. TXNIP restoration sensitizes CML cells to imatinib treatment and compromises imatinib resistant CML cell survival, predominantly through the blockage of both glycolysis and glucose oxidation which results in the mitochondrial dysfunction and ATP production. In particular, TXNIP suppresses expressions of the key glycolytic enzyme, HK2 and LDHA, potentially through Fbw7-dependent c-Myc degradation. In accordance, BCR-ABL suppression of TXNIP provides a novel survival pathway for the transformation of mouse BM cells. Combination of drug inducing TXNIP expression with imatinib synergistically kills CML cells from patients and further extends the survival of CML mice. Thus, the activation of TXNIP represents an effective strategy for CML treatment to overcome resistance.

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