18 results on '"Curik N"'
Search Results
2. 5-Azacitidine in aggressive myelodysplastic syndromes regulates chromatin structure at PU.1 gene and cell differentiation capacity
- Author
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Curik, N, Burda, P, Vargova, K, Pospisil, V, Belickova, M, Vlckova, P, Savvulidi, F, Necas, E, Hajkova, H, Haskovec, C, Cermak, J, Krivjanska, M, Trneny, M, Laslo, P, Jonasova, A, and Stopka, T
- Published
- 2012
- Full Text
- View/download PDF
3. P-003 Transcription factor CTCF inhibits effects of 5-Azacitidine at PU.1 gene in MDS
- Author
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Kapalova, M., primary, Burda, P., additional, Vargova, K., additional, Vargova, J., additional, Savvulidi, F., additional, Zikmund, T., additional, Curik, N., additional, Jonasova, A., additional, and Stopka, T., additional
- Published
- 2013
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4. 52 Chromatin structure at PU.l gene and cell differentiation capacity in myelodysplastic syndrome treated by 5-azacytidine
- Author
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Stopka, T., primary, Curik, N., additional, Burda, P., additional, Vargova, K., additional, Pospisil, V., additional, Hajkova, H., additional, Sawulidi, F., additional, Necas, E., additional, Belickova, M., additional, Haskovec, C., additional, Cermak, J., additional, Trneny, M., additional, and Jonasova, A., additional
- Published
- 2011
- Full Text
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5. Interferon-α Revisited: Individualized Treatment Management Eased the Selective Pressure of Tyrosine Kinase Inhibitors on BCR-ABL1 Mutations Resulting in a Molecular Response in High-Risk CML Patients
- Author
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Martin Novak, Hana Klamova, Simona Soverini, Katerina Machova Polakova, Nikola Curik, Jan Zach, Martina Divoka, Vaclava Polivkova, Edgar Faber, Peter Rohon, Iuri Marinov, O. Černá, Polivkova, V, Rohon, P, Klamova, H, Cerna, O, Divoka, M, Curik, N, Zach, J, Novak, M, Marinov, I, Soverini, S, Faber, E, and Machova Polakova, K.
- Subjects
Male ,CHROMOSOME-POSITIVE LEUKEMIA ,Fusion Proteins, bcr-abl ,Cancer Treatment ,lcsh:Medicine ,NK cells ,White Blood Cells ,DASATINIB THERAPY ,chemistry.chemical_compound ,0302 clinical medicine ,DOMAIN ,Animal Cells ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Medicine and Health Sciences ,Blood and Lymphatic System Procedures ,Precision Medicine ,lcsh:Science ,Immune Response ,Bone Marrow Transplantation ,Aged, 80 and over ,Multidisciplinary ,T Cells ,Stem Cell Therapy ,CHRONIC MYELOGENOUS LEUKEMIA ,Ponatinib ,High-Throughput Nucleotide Sequencing ,Myeloid leukemia ,Middle Aged ,Dasatinib ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Female ,Cellular Types ,medicine.symptom ,Tyrosine kinase ,Research Article ,medicine.drug ,Adult ,Immune Cells ,Immunology ,Surgical and Invasive Medical Procedures ,COMPOUND MUTATIONS ,Research and Analysis Methods ,IMATINIB ,MECHANISMS ,Young Adult ,03 medical and health sciences ,Immune system ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Genetics ,medicine ,Humans ,Point Mutation ,Molecular Biology Techniques ,CHRONIC MYELOID-LEUKEMIA ,Protein Kinase Inhibitors ,Molecular Biology ,Aged ,Clinical Genetics ,Transplantation ,Blood Cells ,business.industry ,Point mutation ,lcsh:R ,Interferon-alpha ,Biology and Life Sciences ,Cell Biology ,Mechanism of action ,chemistry ,Molecular Response ,Mutation ,CELLS ,Cancer research ,lcsh:Q ,business ,RESISTANCE ,Cloning ,030215 immunology - Abstract
Bone marrow transplantation or ponatinib treatment are currently recommended strategies for management of patients with chronic myeloid leukemia (CML) harboring the T315I mutation and compound or polyclonal mutations. However, in some individual cases, these treatment scenarios cannot be applied. We used an alternative treatment strategy with interferon-α (IFN-α) given solo, sequentially or together with TKI in a group of 6 cases of high risk CML patients, assuming that the TKI-independent mechanism of action may lead to mutant clone repression. IFN-α based individualized therapy decreases of T315I or compound mutations to undetectable levels as assessed by next-generation deep sequencing, which was associated with a molecular response in 4/6 patients. Based on the observed results from immune profiling, we assumed that the principal mechanism leading to the success of the treatment was the immune activation induced with dasatinib pre-treatment followed by restoration of immunological surveillance after application of IFN-α therapy. Moreover, we showed that sensitive measurement of mutated BCR-ABL1 transcript levels augments the safety of this individualized treatment strategy.
- Published
- 2016
6. Imatinib therapy of chronic myeloid leukemia significantly reduces carnitine cell intake, resulting in adverse events.
- Author
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Burda P, Hlavackova A, Polivkova V, Curik N, Laznicka A, Krizkova J, Suttnar J, Klener P, and Polakova KM
- Subjects
- Animals, Humans, Mice, Cell Line, Tumor, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacology, Energy Metabolism drug effects, Male, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors adverse effects, Mitochondria metabolism, Mitochondria drug effects, Carnitine metabolism, Carnitine pharmacology, Imatinib Mesylate pharmacology, Imatinib Mesylate adverse effects, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism, Solute Carrier Family 22 Member 5 metabolism
- Abstract
Objective: A prominent, safe and efficient therapy for patients with chronic myeloid leukemia (CML) is inhibiting oncogenic protein BCR::ABL1 in a targeted manner with imatinib, a tyrosine kinase inhibitor. A substantial part of patients treated with imatinib report skeletomuscular adverse events affecting their quality of life. OCTN2 membrane transporter is involved in imatinib transportation into the cells. At the same time, the crucial physiological role of OCTN2 is cellular uptake of carnitine which is an essential co-factor for the mitochondrial β-oxidation pathway. This work investigates the impact of imatinib treatment on carnitine intake and energy metabolism of muscle cells., Methods: HTB-153 (human rhabdomyosarcoma) cell line and KCL-22 (CML cell line) were used to study the impact of imatinib treatment on intracellular levels of carnitine and vice versa. The energy metabolism changes in cells treated by imatinib were quantified and compared to changes in cells exposed to highly specific OCTN2 inhibitor vinorelbine. Mouse models were used to test whether in vitro observations are also achieved in vivo in thigh muscle tissue. The analytes of interest were quantified using a Prominence HPLC system coupled with a tandem mass spectrometer., Results: This work showed that through the carnitine-specific transporter OCTN2, imatinib and carnitine intake competed unequally and intracellular carnitine concentrations were significantly reduced. In contrast, carnitine preincubation did not influence imatinib cell intake or interfere with leukemia cell targeting. Blocking the intracellular supply of carnitine with imatinib significantly reduced the production of most Krebs cycle metabolites and ATP. However, subsequent carnitine supplementation rescued mitochondrial energy production. Due to specific inhibition of OCTN2 activity, the influx of carnitine was blocked and mitochondrial energy metabolism was impaired in muscle cells in vitro and in thigh muscle tissue in a mouse model., Conclusions: This preclinical experimental study revealed detrimental effect of imatinib on carnitine-mediated energy metabolism of muscle cells providing a possible molecular background of the frequently occurred side effects during imatinib therapy such as fatigue, muscle pain and cramps., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
7. Blockage of BCL-XL overcomes venetoclax resistance across BCL2+ lymphoid malignancies irrespective of BIM status.
- Author
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Dolnikova A, Kazantsev D, Klanova M, Pokorna E, Sovilj D, Kelemen CD, Tuskova L, Hoferkova E, Mraz M, Helman K, Curik N, Machova Polakova K, Andera L, Trneny M, and Klener P
- Subjects
- Humans, Animals, Mice, Cell Line, Tumor, Proto-Oncogene Proteins c-bcl-2 metabolism, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Xenograft Model Antitumor Assays, Apoptosis drug effects, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Drug Synergism, Isoquinolines, Benzothiazoles, Sulfonamides pharmacology, Sulfonamides therapeutic use, bcl-X Protein metabolism, bcl-X Protein antagonists & inhibitors, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Bcl-2-Like Protein 11 metabolism, Bcl-2-Like Protein 11 genetics, Drug Resistance, Neoplasm
- Abstract
Abstract: Venetoclax (VEN), a B-cell lymphoma 2 (BCL2) inhibitor, has a promising single-agent activity in mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), and large BCLs, but remissions were generally short, which call for rational drug combinations. Using a panel of 21 lymphoma and leukemia cell lines and 28 primary samples, we demonstrated strong synergy between VEN and A1155463, a BCL-XL inhibitor. Immunoprecipitation experiments and studies on clones with knockout of expression or transgenic expression of BCL-XL confirmed its key role in mediating inherent and acquired VEN resistance. Of note, the VEN and A1155463 combination was synthetically lethal even in the cell lines with lack of expression of the proapoptotic BCL2L11/BIM and in the derived clones with genetic knockout of BCL2L11/BIM. This is clinically important because BCL2L11/BIM deletion, downregulation, or sequestration results in VEN resistance. Immunoprecipitation experiments further suggested that the proapoptotic effector BAX belongs to principal mediators of the VEN and A1155463 mode of action in the BIM-deficient cells. Lastly, the efficacy of the new proapoptotic combination was confirmed in vivo on a panel of 9 patient-derived lymphoma xenografts models including MCL (n = 3), B-ALL (n = 2), T-ALL (n = 1), and diffuse large BCL (n = 3). Because continuous inhibition of BCL-XL causes thrombocytopenia, we proposed and tested an interrupted 4 days on/3 days off treatment regimen, which retained the desired antitumor synergy with manageable platelet toxicity. The proposed VEN and A1155463 combination represents an innovative chemotherapy-free regimen with significant preclinical activity across diverse BCL2+ hematologic malignancies irrespective of the BCL2L11/BIM status., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2024
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8. Combination therapies with ponatinib and asciminib in a preclinical model of chronic myeloid leukemia blast crisis with compound mutations.
- Author
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Curik N, Laznicka A, Polivkova V, Krizkova J, Pokorna E, Semerak P, Suchankova P, Burda P, Hochhaus A, and Machova Polakova K
- Subjects
- Humans, Animals, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Mice, Fusion Proteins, bcr-abl genetics, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors pharmacology, Niacinamide analogs & derivatives, Pyrazoles, Pyridazines therapeutic use, Pyridazines administration & dosage, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Imidazoles therapeutic use, Imidazoles administration & dosage, Mutation, Blast Crisis genetics, Blast Crisis drug therapy, Blast Crisis pathology
- Published
- 2024
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9. The SNP rs460089 in the gene promoter of the drug transporter OCTN1 has prognostic value for treatment-free remission in chronic myeloid leukemia patients treated with imatinib.
- Author
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Machova Polakova K, Albeer A, Polivkova V, Krutska M, Vlcanova K, Curik N, Fabarius A, Klamova H, Spiess B, Waller CF, Brümmendorf TH, Dengler J, Kunzmann V, Burchert A, Belohlavkova P, Mustjoki S, Faber E, Mayer J, Zackova D, Panayiotidis P, Richter J, Hjorth-Hansen H, Kamińska M, Płonka M, Szczepanek E, Szarejko M, Bober G, Hus I, Grzybowska-Izydorczyk O, Wasilewska E, Paczkowska E, Niesiobędzka-Krężel J, Giannopoulos K, Mahon FX, Sacha T, Saußele S, and Pfirrmann M
- Subjects
- Humans, Imatinib Mesylate therapeutic use, Prognosis, Protein Kinase Inhibitors therapeutic use, Membrane Transport Proteins therapeutic use, Treatment Outcome, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Antineoplastic Agents adverse effects
- Abstract
Membrane transporters are important determinants of drug bioavailability. Their expression and activity affect the intracellular drug concentration in leukemic cells impacting response to therapy. Pharmacogenomics represents genetic markers that reflect allele arrangement of genes encoding drug transporters associated with treatment response. In previous work, we identified SNP rs460089 located in the promotor of SLC22A4 gene encoding imatinib transporter OCTN1 as influential on response of patients with chronic myeloid leukemia treated with imatinib. Patients with rs460089-GC pharmacogenotype had significantly superior response to first-line imatinib treatment compared to patients with rs460089-GG. This study investigated whether pharmacogenotypes of rs460089 are associated with sustainability of treatment-free remission (TFR) in patients from the EUROpean Stop Kinase Inhibitor (EURO-SKI) trial. In the learning sample, 176 patients showed a significantly higher 6-month probability of molecular relapse free survival (MRFS) in patients with GC genotype (73%, 95% CI: 60-82%) compared to patients with GG (51%, 95% CI: 41-61%). Also over time, patients with GC genotype had significantly higher MRFS probabilities compared with patients with GG (HR: 0.474, 95% CI: 0.280-0.802, p = 0.0054). Both results were validated with data on 93 patients from the Polish STOP imatinib study. In multiple regression models, in addition to the investigated genotype, duration of TKI therapy (EURO-SKI trial) and duration of deep molecular response (Polish study) were identified as independent prognostic factors. The SNP rs460089 was found as an independent predictor of TFR., (© 2023. The Author(s).)
- Published
- 2024
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10. Somatic Mutations in Oncogenes Are in Chronic Myeloid Leukemia Acquired De Novo via Deregulated Base-Excision Repair and Alternative Non-Homologous End Joining.
- Author
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Curik N, Polivkova V, Burda P, Koblihova J, Laznicka A, Kalina T, Kanderova V, Brezinova J, Ransdorfova S, Karasova D, Rejlova K, Bakardjieva M, Kuzilkova D, Kundrat D, Linhartova J, Klamova H, Salek C, Klener P, Hrusak O, and Machova Polakova K
- Abstract
Somatic mutations are a common molecular mechanism through which chronic myeloid leukemia (CML) cells acquire resistance to tyrosine kinase inhibitors (TKIs) therapy. While most of the mutations in the kinase domain of BCR-ABL1 can be successfully managed, the recurrent somatic mutations in other genes may be therapeutically challenging. Despite the major clinical relevance of mutation-associated resistance in CML, the mechanisms underlying mutation acquisition in TKI-treated leukemic cells are not well understood. This work demonstrated de novo acquisition of mutations on isolated single-cell sorted CML clones growing in the presence of imatinib. The acquisition of mutations was associated with the significantly increased expression of the LIG1 and PARP1 genes involved in the error-prone alternative nonhomologous end-joining pathway, leading to genomic instability, and increased expression of the UNG , FEN and POLD3 genes involved in the base-excision repair (long patch) pathway, allowing point mutagenesis. This work showed in vitro and in vivo that de novo acquisition of resistance-associated mutations in oncogenes is the prevalent method of somatic mutation development in CML under TKIs treatment., Competing Interests: HK was a consultant for and received honoraria from Novartis. KMP was a consultant for and received honoraria from Incyte and Angelini. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Curik, Polivkova, Burda, Koblihova, Laznicka, Kalina, Kanderova, Brezinova, Ransdorfova, Karasova, Rejlova, Bakardjieva, Kuzilkova, Kundrat, Linhartova, Klamova, Salek, Klener, Hrusak and Machova Polakova.)
- Published
- 2021
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11. Sensitivity and reliability of DNA-based mutation analysis by allele-specific digital PCR to follow resistant BCR-ABL1-positive cells.
- Author
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Polivkova V, Benesova A, Zizkova H, Koblihova J, Curik N, Motlova E, Klamova H, Salek C, and Machova Polakova K
- Subjects
- Alleles, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Prognosis, DNA Mutational Analysis methods, Drug Resistance, Neoplasm genetics, Fusion Proteins, bcr-abl genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Mutation, Polymerase Chain Reaction methods, Protein Kinase Inhibitors pharmacology
- Published
- 2021
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12. BCR-ABL1 mediated miR-150 downregulation through MYC contributed to myeloid differentiation block and drug resistance in chronic myeloid leukemia.
- Author
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Srutova K, Curik N, Burda P, Savvulidi F, Silvestri G, Trotta R, Klamova H, Pecherkova P, Sovova Z, Koblihova J, Stopka T, Perrotti D, and Polakova KM
- Subjects
- Adult, Aged, Cell Differentiation drug effects, Cell Differentiation genetics, Cell Line, Tumor, Cell Proliferation drug effects, Cell Proliferation genetics, Down-Regulation drug effects, Drug Resistance, Neoplasm drug effects, Female, Gene Expression Regulation, Leukemic drug effects, HL-60 Cells, Humans, K562 Cells, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Male, Middle Aged, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Protein Kinase Inhibitors pharmacology, Drug Resistance, Neoplasm genetics, Fusion Proteins, bcr-abl genetics, Genes, myc genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, MicroRNAs genetics
- Abstract
The fusion oncoprotein BCR-ABL1 exhibits aberrant tyrosine kinase activity and it has been proposed that it deregulates signaling networks involving both transcription factors and non-coding microRNAs that result in chronic myeloid leukemia (CML). Previously, microRNA expression profiling showed deregulated expression of miR-150 and miR-155 in CML. In this study, we placed these findings into the broader context of the MYC/miR-150/MYB/miR-155/PU.1 oncogenic network. We propose that up-regulated MYC and miR-155 in CD34
+ leukemic stem and progenitor cells, in concert with BCR-ABL1, impair the molecular mechanisms of myeloid differentiation associated with low miR-150 and PU.1 levels. We revealed that MYC directly occupied the -11.7 kb and -0.35 kb regulatory regions in the MIR150 gene. MYC occupancy was markedly increased through BCR-ABL1 activity, causing inhibition of MIR150 gene expression in CML CD34+ and CD34- cells. Furthermore, we found an association between reduced miR-150 levels in CML blast cells and their resistance to tyrosine kinase inhibitors (TKIs). Although TKIs successfully disrupted BCR-ABL1 kinase activity in proliferating CML cells, this treatment did not efficiently target quiescent leukemic stem cells. The study presents new evidence regarding the MYC/miR-150/MYB/miR-155/PU.1 leukemic network established by aberrant BCR-ABL1 activity. The key connecting nodes of this network may serve as potential druggable targets to overcome resistance of CML stem and progenitor cells., (Copyright© 2018 Ferrata Storti Foundation.)- Published
- 2018
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13. Genotypes of SLC22A4 and SLC22A5 regulatory loci are predictive of the response of chronic myeloid leukemia patients to imatinib treatment.
- Author
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Jaruskova M, Curik N, Hercog R, Polivkova V, Motlova E, Benes V, Klamova H, Pecherkova P, Belohlavkova P, Vrbacky F, and Machova Polakova K
- Subjects
- Antineoplastic Agents therapeutic use, Cell Line, Tumor, Female, Genotype, High-Throughput Nucleotide Sequencing methods, Humans, Imatinib Mesylate therapeutic use, K562 Cells, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Linkage Disequilibrium, Male, Mutation Rate, Promoter Regions, Genetic, Sequence Analysis, DNA methods, Symporters, Treatment Outcome, Antineoplastic Agents administration & dosage, Imatinib Mesylate administration & dosage, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Organic Cation Transport Proteins genetics, Polymorphism, Single Nucleotide, Solute Carrier Family 22 Member 5 genetics
- Abstract
Background: Through high-throughput next-generation sequencing of promoters of solute carrier and ATP-binding cassette genes, which encode drug transporters, we aimed to identify SNPs associated with the response to imatinib administered for first-line treatment of patients with chronic myeloid leukemia., Methods: In silico analysis using publicly available databases was done to select the SLC and ABC genes and their promoters for the next-generation sequencing. SNPs associated with the imatinib response were identified using Fisher's exact probability tests and subjected to the linkage disequilibrium analyses with regulatory loci of concerned genes. We analyzed cumulative achievement of major molecular response and probability of event free survival in relation to identified SNP genotypes in 129 CML patients and performed multivariate analysis for determination of genotypes as independent predictors of outcome. Gene expression analysis of eight cell lines naturally carrying different genotypes was performed to outline an impact of genotypes on the gene expression., Results: We observed significant differences in the frequencies of the rs460089-GC and rs460089-GG (SLC22A4) genotypes among rs2631365-TC (SLC22A5) genotype carriers that were associated with optimal and non-optimal responses, respectively. Loci rs460089 and rs2631365 were in highly significant linkage disequilibrium with 12 regulatory loci in introns of SLC22A4 and SLC22A5 encoding imatinib transporters. Genotype association analysis with the response to imatinib indicated that rs460089-GC carriers had a significantly higher probability of achieving a stable major molecular response (BCR-ABL1 transcript level below or equal to 0.1% in the international scale). In contrast, the rs460089-GG represented a risk factor for imatinib failure, which was significantly higher in rs460089-GG_rs2631365-TC carriers., Conclusions: This exploratory study depicted potentially important genetic markers predicting outcome of imatinib treatment, which may be helpful for tailoring therapy in clinical practice.
- Published
- 2017
- Full Text
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14. Interferon-α Revisited: Individualized Treatment Management Eased the Selective Pressure of Tyrosine Kinase Inhibitors on BCR-ABL1 Mutations Resulting in a Molecular Response in High-Risk CML Patients.
- Author
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Polivkova V, Rohon P, Klamova H, Cerna O, Divoka M, Curik N, Zach J, Novak M, Marinov I, Soverini S, Faber E, and Machova Polakova K
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols pharmacology, Female, Fusion Proteins, bcr-abl drug effects, High-Throughput Nucleotide Sequencing methods, Humans, Interferon-alpha pharmacology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Male, Middle Aged, Precision Medicine, Protein Kinase Inhibitors pharmacology, Treatment Outcome, Young Adult, Fusion Proteins, bcr-abl genetics, Interferon-alpha administration & dosage, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Protein Kinase Inhibitors administration & dosage
- Abstract
Bone marrow transplantation or ponatinib treatment are currently recommended strategies for management of patients with chronic myeloid leukemia (CML) harboring the T315I mutation and compound or polyclonal mutations. However, in some individual cases, these treatment scenarios cannot be applied. We used an alternative treatment strategy with interferon-α (IFN-α) given solo, sequentially or together with TKI in a group of 6 cases of high risk CML patients, assuming that the TKI-independent mechanism of action may lead to mutant clone repression. IFN-α based individualized therapy decreases of T315I or compound mutations to undetectable levels as assessed by next-generation deep sequencing, which was associated with a molecular response in 4/6 patients. Based on the observed results from immune profiling, we assumed that the principal mechanism leading to the success of the treatment was the immune activation induced with dasatinib pre-treatment followed by restoration of immunological surveillance after application of IFN-α therapy. Moreover, we showed that sensitive measurement of mutated BCR-ABL1 transcript levels augments the safety of this individualized treatment strategy.
- Published
- 2016
- Full Text
- View/download PDF
15. GATA-1 Inhibits PU.1 Gene via DNA and Histone H3K9 Methylation of Its Distal Enhancer in Erythroleukemia.
- Author
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Burda P, Vargova J, Curik N, Salek C, Papadopoulos GL, Strouboulis J, and Stopka T
- Subjects
- Cell Differentiation genetics, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases genetics, DNA (Cytosine-5-)-Methyltransferases metabolism, DNA Methylation genetics, Enhancer Elements, Genetic, GATA1 Transcription Factor metabolism, Gene Expression Regulation, Leukemic, Histones genetics, Humans, Leukemia, Erythroblastic, Acute pathology, Leukemia, Myeloid, Acute pathology, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins biosynthesis, Proto-Oncogene Proteins metabolism, Trans-Activators biosynthesis, Trans-Activators metabolism, Transcription, Genetic, GATA1 Transcription Factor genetics, Leukemia, Erythroblastic, Acute genetics, Leukemia, Myeloid, Acute genetics, Proto-Oncogene Proteins genetics, Trans-Activators genetics
- Abstract
GATA-1 and PU.1 are two important hematopoietic transcription factors that mutually inhibit each other in progenitor cells to guide entrance into the erythroid or myeloid lineage, respectively. PU.1 controls its own expression during myelopoiesis by binding to the distal URE enhancer, whose deletion leads to acute myeloid leukemia (AML). We herein present evidence that GATA-1 binds to the PU.1 gene and inhibits its expression in human AML-erythroleukemias (EL). Furthermore, GATA-1 together with DNA methyl Transferase I (DNMT1) mediate repression of the PU.1 gene through the URE. Repression of the PU.1 gene involves both DNA methylation at the URE and its histone H3 lysine-K9 methylation and deacetylation as well as the H3K27 methylation at additional DNA elements and the promoter. The GATA-1-mediated inhibition of PU.1 gene transcription in human AML-EL mediated through the URE represents important mechanism that contributes to PU.1 downregulation and leukemogenesis that is sensitive to DNA demethylation therapy.
- Published
- 2016
- Full Text
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16. Epigenetic control of SPI1 gene by CTCF and ISWI ATPase SMARCA5.
- Author
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Dluhosova M, Curik N, Vargova J, Jonasova A, Zikmund T, and Stopka T
- Subjects
- Acute Disease, Adenosine Triphosphatases metabolism, Animals, Azacitidine pharmacology, CCCTC-Binding Factor, Cell Line, Tumor, Chromosomal Proteins, Non-Histone metabolism, DNA Methylation drug effects, Gene Expression Regulation, Neoplastic, Genomic Imprinting, HeLa Cells, Humans, Immunoblotting, Insulin-Like Growth Factor II genetics, Insulin-Like Growth Factor II metabolism, K562 Cells, Leukemia, Erythroblastic, Acute genetics, Leukemia, Erythroblastic, Acute metabolism, Leukemia, Erythroblastic, Acute pathology, Leukemia, Myeloid genetics, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Microscopy, Confocal, Protein Binding, Proto-Oncogene Proteins metabolism, RNA Interference, RNA, Long Noncoding genetics, RNA, Long Noncoding metabolism, Repressor Proteins metabolism, Reverse Transcriptase Polymerase Chain Reaction, Trans-Activators metabolism, Adenosine Triphosphatases genetics, Chromosomal Proteins, Non-Histone genetics, Epigenesis, Genetic, Proto-Oncogene Proteins genetics, Repressor Proteins genetics, Trans-Activators genetics
- Abstract
CCCTC-binding factor (CTCF) can both activate as well as inhibit transcription by forming chromatin loops between regulatory regions and promoters. In this regard, Ctcf binding on non-methylated DNA and its interaction with the Cohesin complex results in differential regulation of the H19/Igf2 locus. Similarly, a role for CTCF has been established in normal hematopoietic development; however its involvement in leukemia remains elusive. Here, we show that Ctcf binds to the imprinting control region of H19/Igf2 in AML blasts. We also demonstrate that Smarca5, which also associates with the Cohesin complex, facilitates Ctcf binding to its target sites on DNA. Furthermore, Smarca5 supports Ctcf functionally and is needed for enhancer-blocking effect at ICR. We next asked whether CTCF and SMARCA5 control the expression of key hematopoiesis regulators. In normally differentiating myeloid cells both CTCF and SMARCA5 together with members of the Cohesin complex are recruited to the SPI1 gene, a key hematopoiesis regulator and leukemia suppressor. Due to DNA methylation, CTCF binding to the SPI1 gene is blocked in AML blasts. Upon AZA-mediated DNA demethylation of human AML blasts, CTCF and SMARCA5 are recruited to the -14.4 Enhancer of SPI1 gene and block its expression. Our data provide new insight into complex SPI1 gene regulation now involving additional key epigenetic factors, CTCF and SMARCA5 that control PU.1 expression at the -14.4 Enhancer.
- Published
- 2014
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17. MYB transcriptionally regulates the miR-155 host gene in chronic lymphocytic leukemia.
- Author
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Vargova K, Curik N, Burda P, Basova P, Kulvait V, Pospisil V, Savvulidi F, Kokavec J, Necas E, Berkova A, Obrtlikova P, Karban J, Mraz M, Pospisilova S, Mayer J, Trneny M, Zavadil J, and Stopka T
- Subjects
- Chromatin chemistry, Chromatin genetics, Chromatin metabolism, Cluster Analysis, Gene Expression Profiling, Gene Expression Regulation, Leukemic, HeLa Cells, Humans, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Microarray Analysis, Oncogene Proteins v-myb metabolism, Promoter Regions, Genetic, Protein Binding, Transcription, Genetic physiology, Transfection, Tumor Cells, Cultured, Leukemia, Lymphocytic, Chronic, B-Cell genetics, MicroRNAs genetics, Oncogene Proteins v-myb physiology
- Abstract
Elevated levels of microRNA miR-155 represent a candidate pathogenic factor in chronic B-lymphocytic leukemia (B-CLL). In this study, we present evidence that MYB (v-myb myeloblastosis viral oncogene homolog) is overexpressed in a subset of B-CLL patients. MYB physically associates with the promoter of miR-155 host gene (MIR155HG, also known as BIC, B-cell integration cluster) and stimulates its transcription. This coincides with the hypermethylated histone H3K4 residue and spread hyperacetylation of H3K9 at MIR155HG promoter. Our data provide evidence of oncogenic activities of MYB in B-CLL that include its stimulatory role in MIR155HG transcription.
- Published
- 2011
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18. PU.1 activation relieves GATA-1-mediated repression of Cebpa and Cbfb during leukemia differentiation.
- Author
-
Burda P, Curik N, Kokavec J, Basova P, Mikulenkova D, Skoultchi AI, Zavadil J, and Stopka T
- Subjects
- CCAAT-Enhancer-Binding Proteins metabolism, Cell Differentiation genetics, Cell Transformation, Neoplastic metabolism, Core Binding Factor beta Subunit metabolism, GATA1 Transcription Factor metabolism, Gene Expression Regulation, Neoplastic genetics, HeLa Cells, Histones genetics, Histones metabolism, Humans, Leukemia metabolism, Leukemia physiopathology, Myeloid Cells metabolism, RNA Interference, RNA, Small Interfering, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Regulatory Elements, Transcriptional genetics, Repressor Proteins genetics, Repressor Proteins metabolism, Transcriptional Activation genetics, CCAAT-Enhancer-Binding Proteins genetics, Cell Transformation, Neoplastic genetics, Core Binding Factor beta Subunit genetics, GATA1 Transcription Factor genetics, Leukemia genetics, Proto-Oncogene Proteins genetics, Trans-Activators genetics
- Abstract
Hematopoietic transcription factors GATA-1 and PU.1 bind each other on DNA to block transcriptional programs of undesired lineage during hematopoietic commitment. Murine erythroleukemia (MEL) cells that coexpress GATA-1 and PU.1 are blocked at the blast stage but respond to molecular removal (downregulation) of PU.1 or addition (upregulation) of GATA-1 by inducing terminal erythroid differentiation. To test whether GATA-1 blocks PU.1 in MEL cells, we have conditionally activated a transgenic PU.1 protein fused with the estrogen receptor ligand-binding domain (PUER), resulting in activation of a myeloid transcriptional program. Gene expression arrays identified components of the PU.1-dependent transcriptome negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein alpha (Cebpa) and core-binding factor, beta subunit (Cbfb), which encode two key hematopoietic transcription factors. Inhibition of GATA-1 by small interfering RNA resulted in derepression of PU.1 target genes. Chromatin immunoprecipitation and reporter assays identified PU.1 motif sequences near Cebpa and Cbfb that are co-occupied by PU.1 and GATA-1 in the leukemic blasts. Significant derepression of Cebpa and Cbfb is achieved in MEL cells by either activation of PU.1 or knockdown of GATA-1. Furthermore, transcriptional regulation of these loci by manipulating the levels of PU.1 and GATA-1 involves quantitative increases in a transcriptionally active chromatin mark: acetylation of histone H3K9. Collectively, we show that either activation of PU.1 or inhibition of GATA-1 efficiently reverses the transcriptional block imposed by GATA-1 and leads to the activation of a myeloid transcriptional program directed by PU.1.
- Published
- 2009
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