Comparison of K562 Chronic Myeloid Leukemia cells with resistant counterparts
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE298575 | GEO | 2025/07/17
REPOSITORIES: GEO
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Project description:Leukemia stem cells (LSC) in chronic myelogenous leukemia (CML) resist elimination with tyrosine kinase inhibitors (TKI) and persist as a source of disease recurrence. LSC populations are heterogeneous, but the most primitive, drug-resistant subsets are not well characterized. Previous studies indicate that variable cell-surface expression of the c-Kit receptor identifies heterogeneous hematopoietic stem cells (HSC) populations. We found that c-Kit expression is reduced on CML LSC compared to normal HSC. Long-term engraftment and leukemia generation capacity was restricted to low c-Kit expressing (c-KitLow) LSC, which showed increased quiescence and inflammatory gene signatures expression. The c-Kit ligand, stem cell factor (SCF), expanded normal HSC but drove maturation of CML LSC. The proportion of c-Kitlow LT-HSC was increased with TKI treatment. Supplementary SCF treatment enhanced elimination of committed but not primitive CML LT-HSC in TKI-treated mice. Low c-Kit expression identifies primitive, treatment-resistant LSC subpopulations with distinct regulatory characteristics, that are critical therapeutic targets.
2022-11-29 | GSE180496 | GEO
Project description:Comparison of K562 Chronic Myeloid Leukemia cells with resistant counterparts
| PRJNA1269965 | ENA
Project description:Chronic myeloid leukemia (CML) is a stem cell-derived malignancy driven by the BCR-ABL oncogene. Imatinib (IM) is a targeted therapy used to treat CML; however, primary resistance and molecular evidence of persistent disease have been observed in some patients. Recent evidence suggests that exosome-derived microRNAs (miRNAs) contribute to drug resistance and may serve as novel biomarkers for cancer diagnosis and drug sensitivity prediction. This study aimed to explore the plasma exosomal miRNA profiles in patients with CML to identify biomarkers associated with IM resistance. Exosomes isolated from the plasma of patients with IM-sensitive and -resistant CML patients were characterized, and exosomal miRNA profiling was conducted using RNA sequencing. Differential expression analysis identified 13 upregulated miRNAs and 21 downregulated miRNAs. Bioinformatics analysis highlighted pathways related to autophagy and PI3K-Akt signaling. Among the upregulated miRNAs, miR-451 and miR-16 were significantly elevated in exosomes from IM-resistant patients compared with those from IM-sensitive patients. Target gene analysis of these miRNAs was performed. Our findings suggest that plasma exosomal miRNAs, particularly miR-451 and miR-16, can serve as potential biomarkers for IM resistance in CML. These results offer new insights into the molecular mechanisms underlying IM resistance and may inform future therapeutic strategies.
2025-03-03 | GSE290959 | GEO
Project description:BCR::ABL1 drives chronic myeloid leukemia (CML) disease and treatment, as revealed by the success of tyrosine kinase inhibitor (TKI) therapy. However, additional poorly characterized molecular pathways, acting as BCR::ABL1 independent nechanisms, play crucial roles in CML, contributing to leukemic stem cells (LSCs) persistence, TKI resistance and disease progression. Here, by combining high sensitive mass spectrometry (MS)-based phosphoproteomics with the SignalingProfiler pipeline, we obtained two signaling maps offering a comprehensive description of the BCR::ABL1 dependent and independent pro-survival signalling mechanisms. We leveraged these maps to unbiasedly and systematically discover therapeutic vulnerabilities, by implementing the Druggability Score computational algorithm. By this strategy, and in combination with in vitro and in ex vivo functional assays, we show a crucial role of acquired FLT3-dependency in resistant CML models. In conclusion, we reposition FLT3, one of the most frequently mutated drivers of acute leukemia, as a potential therapeutic target for TKI resistant CML patients.
2025-03-31 | GSE280476 | GEO
Project description:Acquired imatinib resistance in chronic myelogenous leukemia (CML) can be the consequence of mutations in the kinase domain of BCR-ABL or increased protein levels. However, as in other malignancies, acquired resistance to cytostatic drugs is a common reason for treatment failure or disease progression. As a model for drug resistance, we developed a CML cell line resistant to cyclophosphamide (CP). Using oligonucleotide arrays, we examined changes in global gene expression. Selected genes were also examined by real-time PCR and flow cytometry. Neither the parent nor the resistant lines had mutations in their ATP binding domain. Filtering genes with a low-base line expression, a total of 239 genes showed significant changes (162 up- and 77 down-regulated) in the resistant clone. Most of the up-regulated genes were associated with metabolism, signal transduction, or encoded enzymes. The gene for aldehyde dehydrogenase 1 was over-expressed more than 2000 fold in the resistant clone. BCR-ABL was expressed in both cell lines to a comparable extent. When exposed to the tyrosine kinase inhibitors imatinib and nilotinib, both lines were sensitive. In conclusion, we found multiple genetic changes in a CML cell line resistant to CP related to metabolism, signal transduction or apoptosis. Despite these changes, the resistant cells retained sensitivity to tyrosine kinase inhibitors. Experiment Overall Design: A CML cell line and a CP resistant subline were compared by gene array. In addition other markers, the expression of BCR-ABL and the sensitivity to tyrosine kinase inhibitors were tested.
2009-04-25 | E-GEOD-7114 | biostudies-arrayexpress
Project description:Analysis of the acquired copy number profile in K562 cell which got resistant against HSP90 inhibitors.
| EGAS00001006385 | EGA
Project description:Chronic myeloid leukemia (CML) epitomizes successful targeted therapy, with 86% of patients in the chronic phase treated with tyrosine kinase inhibitors (TKIs) attaining remission. However, resistance to TKIs occurs during treatment, and patients with resistance to TKIs progress to the acute phase called Blast Crisis (BC), wherein the survival is restricted to 7-11 months. About 80 % of patients in BC are unresponsive to TKIs. This issue can be addressed by identifying a molecular signature which can predict resistance in CML-CP prior to treatment as well as by delineating the molecular mechanism underlying resistance. Herein, we report genomic analysis of CML patients and imatinib-resistant K562 cell line to achieve the same. WGS was performed on imatinib-sensitive and -resistant K562 cells. Library preparation was done by 30x WGS KAPA PCR-Free v2.1 kit, and Illumina HiSeq X sequencer was used for 2 x 150 bp paired-end sequencing. Our study identified accumulation of aberrations on chromosomes 1, 3, 7, 16 and 22 as predictive of occurrence of resistance. Further, recurrent amplification in chromosomal region 8q11.2-12.1 was detected in highly resistant K562 cells as well as CML patients. The genes present in this region were analyzed to understand molecular mechanism of imatinib resistance.
2024-01-01 | E-MTAB-11896 | biostudies-arrayexpress
Project description:Background: Tyrosine kinase inhibitor (TKI) resistance is a significant factor exacerbating the burden on chronic myeloid leukemia (CML) patients and impacting clinical efficacy. The main goal is to offer new insights into overcoming drug resistance in treating CML. Methods: (IM) resistant K562/IM cells were generated using gradient induction. Responses to IM, lycorine, and autophagy modulators were assessed using CCK-8. Protein expression of Beclin-1, Atg5, LC3, Caspase-3, P62, Bax, Bcl-2, and P-gp was detected using Western blot. Lycorine-induced apoptosis and cell cycle changes were evaluated through flow cytometry, while autophagy alterations were detected using Monodansylcadaverine(MDC) staining. In the K562/IM mice model, Non-obese diabetic severe combined immunodeficent(NOD-SCID) mice were subcutaneously inoculated with K562/IM cells. After 17 days of lycorine injection, assessments included tumor size, Hematoxylin-eosin(HE) staining, and Ki67 expression. Results: After 72 hours of IM treatment, K562/IM cells showed a 55.86-fold increase in drug resistance compared to K562 cells. Lycorine treatment for 24 hours inhibited cell proliferation and induced G0/G1 phase cell cycle arrest and apoptosis in both K562 and K562/IM cells. MDC staining indicated reduced autophagy in K562/IM cells, mitigated by lycorine. In vivo experiments demonstrated reduced tumor size and Ki67 proliferation index in the lycorine treatment group (K562+L, K562/IM+L) compared to the control group, particularly in the drug-resistant group. However, no significant change in Ki67 was observed in the K562 group after lycorine treatment. Conclusion: In summary, K562/IM cells displayed heightened autophagy levels compared to K562 cells. Lycorine effectively impeded the proliferation of K562/IM cells through diverse mechanisms, including reduced autophagy, enhanced apoptosis, and induced cell cycle arrest.
2024-05-20 | GSE267522 | GEO
Project description:Acquired imatinib resistance in chronic myelogenous leukemia (CML) can be the consequence of mutations in the kinase domain of BCR-ABL or increased protein levels. However, as in other malignancies, acquired resistance to cytostatic drugs is a common reason for treatment failure or disease progression. As a model for drug resistance, we developed a CML cell line resistant to cyclophosphamide (CP). Using oligonucleotide arrays, we examined changes in global gene expression. Selected genes were also examined by real-time PCR and flow cytometry. Neither the parent nor the resistant lines had mutations in their ATP binding domain. Filtering genes with a low-base line expression, a total of 239 genes showed significant changes (162 up- and 77 down-regulated) in the resistant clone. Most of the up-regulated genes were associated with metabolism, signal transduction, or encoded enzymes. The gene for aldehyde dehydrogenase 1 was over-expressed more than 2000 fold in the resistant clone. BCR-ABL was expressed in both cell lines to a comparable extent. When exposed to the tyrosine kinase inhibitors imatinib and nilotinib, both lines were sensitive. In conclusion, we found multiple genetic changes in a CML cell line resistant to CP related to metabolism, signal transduction or apoptosis. Despite these changes, the resistant cells retained sensitivity to tyrosine kinase inhibitors. Keywords: Cell type comparison
2007-02-24 | GSE7114 | GEO
Project description:Purpose: We previously demonstrated that immunophenotypically CD34-CD38- TKI resistant LSC/LIC population was clearly heterogeneous. The goal of this study is to explore more about the drug-resistant LSC/LICs Methods: CML patient cells were treated for 7 days with imatinib and live cells were subjected to scRNA-sequencing Results: scRNA-seq reveals heterogeneity in the therapy resistant cells. Distinct expression profiles, yet with an interrelated continuumsuggest the existence of a depply-quiescent persister population within resistant cells. Conclusions: In this study using single cell transcriptomics and single cell metabolomics analyses we identify and characterize a deeply-quiescent/persister CML LSC/LIC population subset of CML patient cells which is highly dependent on FAO for their metabolomic requierements
2023-06-16 | GSE206421 | GEO