Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA121005 | ENA |
REPOSITORIES: ENA
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Project description:To elucidate whether tyrosine kinase inhibitor (TKI) resistance in CML is associated with characteristic genomic alterations, we analyzed DNA samples from 45 TKI resistant CML patients with 250K single nucleotide polymorphism (SNP) arrays. From 20 patients, matched serial samples of pre-treatment and TKI resistance time points were available. 11 of the 45 TKI resistant patients had mutations of BCR-ABL1, including two T315I mutations. Besides known TKI resistance associated genomic lesions such as duplication of the BCR-ABL1 gene (n=8) and trisomy 8 (n=3), recurrent submicroscopic alterations including acquired uniparental disomy were detectable on chromosomes 1, 8, 9, 17, 19 and 22. On chromosome 22, newly acquired and recurrent deletions of the IGLC1 locus were detected in three patients, who had previously presented with lymphoid or myeloid blast crisis. This may support a hypothesis of TKI induced selection of subclones differentiating into immature B-cell progenitors as a mechanism of disease progression and evasion of TKI sensitivity. Keywords: SNP-chip
2010-02-09 | GSE18964 | GEO
Project description:Chronic myelogenous leukemia (CML) is a malignant stem cell disease characterized by a reciprocal translocation between chromosome 9 and 22. The selective bcr-abl tyrosine-kinase inhibitor Imatinib has become the therapy of choice for patients with newly diagnosed CML including those previously considered candidates for allogeneic haematopoietic stem cell transplantation. The tyrosine-kinase inhibitor Nilotinib is a derivate of Imatinib with higher potency. To examine the molecular and functional effects of Nilotinib and Imatinib in chronic myelogenous leukemia, we performed gene expression and functional analyses in K562 cells following treatment with the two tyrosine kinase inhibitors. Experiment Overall Design: Affymetrix U133A 2.0 microarrays were used to examine the gene expression profile of K562 cells after in vitro treatment with Imatinib (0.5 µM) or Nilotinib (0.05 µM) for 24 hours. Gene expression data of the treated cells were compared with data of untreated cells.
2010-01-19 | E-GEOD-19567 | biostudies-arrayexpress
Project description:Increased FTO expression has been connected to resistance to tyrosine kinase inhibitors in CML. To explore the therapeutic potential of targeting FTO in CML, we tested the FTO catalytic inhibitor in the K562 CML cell line. The RNA-seq was performed to identify relevant regulated genes.
2023-12-31 | E-MTAB-12774 | biostudies-arrayexpress
Project description:Chronic Myeloid Leukemia (CML) remains a therapeutic challenge, particularly in patients who develop resistance to standard tyrosine kinase inhibitors (TKIs) such as imatinib. Here, we present the first demonstration of the potent anti-leukemic activity of the histone deacetylase (HDAC) inhibitor martinostat in both TKI-sensitive and TKI-resistant CML. Structural and biochemical analyses confirmed the efficient and selective binding of martinostat to HDAC isoenzyme ligand-binding pockets, resulting in histone and tubulin hyperacetylation in both imatinib-sensitive and resistant CML cells, outperforming vorinostat, a clinically used HDAC inhibitor (HDACi). It selectively impaired CML cell proliferation and viability and induced apoptosis across various CML models, including resistant cell models and patient blasts, with minimal toxicity to healthy cells and low developmental toxicity in zebrafish. In addition to its single-agent efficacy, martinostat demonstrated enhanced anticancer effects when combined with imatinib, both in vitro and in vivo, significantly reducing tumor growth in resistant CML xenograft models. Mechanistically, mRNA-seq data showed that martinostat disrupted key survival signaling pathways and amplified apoptotic responses, thereby contributing to its anticancer activity. These findings highlight the potential of martinostat as a selective, low-toxicity HDACi that, when combined with TKIs, could provide an effective strategy to overcome drug resistance in CML and improve therapeutic outcomes.
2025-07-23 | GSE292088 | 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:Current treatment for CML involves tyrosine kinase inhibitors (TKIs), which turned it into a managable disease. In a transcriptional profile of TKI-resistant versus newly diagnosed CML patient samples, G0S2 was shown to be profoundly downregulated.
2021-04-13 | GSE171945 | GEO
Project description:Chronic myelogenous leukemia (CML) is a malignant stem cell disease characterized by a reciprocal translocation between chromosome 9 and 22. The selective bcr-abl tyrosine-kinase inhibitor Imatinib has become the therapy of choice for patients with newly diagnosed CML including those previously considered candidates for allogeneic haematopoietic stem cell transplantation. The tyrosine-kinase inhibitor Nilotinib is a derivate of Imatinib with higher potency. To examine the molecular and functional effects of Nilotinib and Imatinib in chronic myelogenous leukemia, we performed gene expression and functional analyses in K562 cells following treatment with the two tyrosine kinase inhibitors.
2009-12-19 | GSE19567 | GEO
Project description:Chronic myeloid leukaemia (CML) is a clonal haemopoietic stem cell (HSC) disorder associated with the BCR-ABL oncogene, which encodes a constitutively active tyrosine kinase. We have demonstrated the existence of CML HSC which are resistant to the tyrosine kinase inhibitors (TKI). We have hypothesised that CML stem cells are dependent on key survival pathways that are induced by TKI treatment. In order to elucidate these key survival pathways, we have investigated the transcriptional differences between normal and CML stem/progenitor cells (CD34+38-) and by carrying out RNA profiling for the different populations. CD34+38- cells were isolated from chronic phase patient samples. LCSciences human miRNA microarray chips were used (100% coverage of mature miRNAs listed in miRBase version 14).
2018-01-12 | E-MTAB-3220 | biostudies-arrayexpress
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. Thirteen CML patients (sensitive and resistant to TKIs) and 2 BMT donors (as control) were recruited for the study. DNA was isolated from an enriched CD34+ fraction for each sample as well as from K562 cells made resistant to imatinib which provided a model system for further molecular investigations. DNA was subjected to Cytoscan HD array (Affymatrix) analysis from patient samples and cell lines. Affymetrix CytoScan™ HD array (Applied Biosystems™, Cat# 901835) chip consists of 2.6 M oligonucleotide probes across the genome, including 1953K unique non-polymorphic probes and 750K bi-allelic SNP (single nucleotide polymorphism) probes. 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-11899 | biostudies-arrayexpress
Project description:Treatment with demethylating agents in combination with tyrosine kinase inhibitors have shown improved molecular responses and survival benefits in patients with TKI-resistant or advanced-phase CML. However, little is known regarding underlying mechanism of the combination anti-tumor effect of demethylating agents and tyrosine kinase inhibitors. To analyze the combination effect, we have compared gene expression profiles among chronic myeloid leukemia (CML) cell lines (K562, KBM5) treated with imatinib (IM), a new demethylating agent, OR-2100 (OR21), and these combination therapy.
2020-09-09 | GSE157620 | GEO