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2. JAK2V617F but not CALR mutations confer increased molecular responses to interferon-α via JAK1/STAT1 activation

Author

Czech, Julia, Cordua, Sabrina, Weinbergerova, Barbora, Baumeister, Julian, Crepcia, Assja, Han, Lijuan, Maié, Tiago, Costa, Ivan G., Denecke, Bernd, Maurer, Angela, Schubert, Claudia, Feldberg, Kristina, Gezer, Deniz, Brümmendorf, Tim H., Müller-Newen, Gerhard, Mayer, Jiri, Racil, Zdenek, Kubesova, Blanka, Knudsen, Trine, Sørensen, Anders L., Holmström, Morten, Kjær, Lasse, Skov, Vibe, Larsen, Thomas Stauffer, Hasselbalch, Hans C., Chatain, Nicolas, and Koschmieder, Steffen

Published
2019
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3. Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms

Author

Milosevic Feenstra, Jelena D., Nivarthi, Harini, Gisslinger, Heinz, Leroy, Emilie, Rumi, Elisa, Chachoua, Ilyas, Bagienski, Klaudia, Kubesova, Blanka, Pietra, Daniela, Gisslinger, Bettina, Milanesi, Chiara, Jäger, Roland, Chen, Doris, Berg, Tiina, Schalling, Martin, Schuster, Michael, Bock, Christoph, Constantinescu, Stefan N., Cazzola, Mario, and Kralovics, Robert

Published
2016
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5. The Unfolded Protein Response Is a Major Driver of LCN2 Expression in BCR–ABL- and JAK2V617F-Positive MPN

Author

Tillmann, Stefan, primary, Olschok, Kathrin, additional, Schröder, Sarah K., additional, Bütow, Marlena, additional, Baumeister, Julian, additional, Kalmer, Milena, additional, Preußger, Vera, additional, Weinbergerova, Barbora, additional, Kricheldorf, Kim, additional, Mayer, Jiri, additional, Kubesova, Blanka, additional, Racil, Zdenek, additional, Wessiepe, Martina, additional, Eschweiler, Jörg, additional, Isfort, Susanne, additional, Brümmendorf, Tim H., additional, Becker, Walter, additional, Schemionek, Mirle, additional, Weiskirchen, Ralf, additional, Koschmieder, Steffen, additional, and Chatain, Nicolas, additional

Published
2021
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7. Early and late stage MPN patients show distinct gene expression profiles in CD34+ cells.

Author

Baumeister, Julian, Maié, Tiago, Chatain, Nicolas, Gan, Lin, Weinbergerova, Barbora, de Toledo, Marcelo A. S., Eschweiler, Jörg, Maurer, Angela, Mayer, Jiri, Kubesova, Blanka, Racil, Zdenek, Schuppert, Andreas, Costa, Ivan, Koschmieder, Steffen, Brümmendorf, Tim H., and Gezer, Deniz

Subjects
GENE expression profiling, B cells, PROGNOSIS, BLOOD diseases, GENE expression
Abstract

Myeloproliferative neoplasms (MPN), comprising essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), are hematological disorders of the myeloid lineage characterized by hyperproliferation of mature blood cells. The prediction of the clinical course and progression remains difficult and new therapeutic modalities are required. We conducted a CD34+ gene expression study to identify signatures and potential biomarkers in the different MPN subtypes with the aim to improve treatment and prevent the transformation from the rather benign chronic state to a more malignant aggressive state. We report here on a systematic gene expression analysis (GEA) of CD34+ peripheral blood or bone marrow cells derived from 30 patients with MPN including all subtypes (ET (n = 6), PV (n = 11), PMF (n = 9), secondary MF (SMF; post-ET-/post-PV-MF; n = 4)) and six healthy donors. GEA revealed a variety of differentially regulated genes in the different MPN subtypes vs. controls, with a higher number in PMF/SMF (200/272 genes) than in ET/PV (132/121). PROGENγ analysis revealed significant induction of TNFα/NF-κB signaling (particularly in SMF) and reduction of estrogen signaling (PMF and SMF). Consistently, inflammatory GO terms were enriched in PMF/SMF, whereas RNA splicing–associated biological processes were downregulated in PMF. Differentially regulated genes that might be utilized as diagnostic/prognostic markers were identified, such as AREG, CYBB, DNTT, TIMD4, VCAM1, and S100 family members (S100A4/8/9/10/12). Additionally, 98 genes (including CLEC1B, CMTM5, CXCL8, DACH1, and RADX) were deregulated solely in SMF and may be used to predict progression from early to late stage MPN. [ABSTRACT FROM AUTHOR]

Published
2021
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9. Additional file 3: of ToTem: a tool for variant calling pipeline optimization

Author

Tom, Nikola, Tom, Ondrej, Malcikova, Jitka, Sarka Pavlova, Kubesova, Blanka, Rausch, Tobias, Kolarik, Miroslav, Benes, Vladimir, Bystry, Vojtech, and Sarka Pospisilova

Subjects
Hardware_ARITHMETICANDLOGICSTRUCTURES
Abstract

Material and details of pipeline configurations. The document describes in detail the material and pipeline configurations used in the study. (DOCX 48 kb)

Published
2018
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11. Evaluation of two CE-IVD tests for BCR-ABL1 transcript monitoring of chronic myeloid leukemia patients.

Author

Folta, Adam, Jurcek, Tomas, Kubesova, Blanka, Zackova, Daniela, Semerad, Lukas, Mayer, Jiri, and Jeziskova, Ivana

Subjects
CHRONIC myeloid leukemia, REVERSE transcriptase polymerase chain reaction
Abstract

According to European Leukemia Network (ELN) recommendations, real-time quantitative PCR (qRT-PCR) is a conventional strategy for long-term I BCR-ABL1 i transcript monitoring in patients with chronic myeloid leukemia (CML) both during tyrosine kinase inhibitor (TKI) therapy and its discontinuation [[1]]. The samples were divided into two groups according to the conventional qRT-PCR results: 11/58 samples were scored as I BCR-ABL1 i undetectable at the molecular response (MR) level 5.0, and 47/58 samples were scored as I BCR-ABL1 i positive. Graphs A and B show qRT-PCR vs GeneXpert comparison, graphs C and D qRT-PCR vs ddPCR comparison, and graphs E and F GeneXpert vs ddPCR comparison. [Extracted from the article]

Published
2021
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12. Higher rates of molecular response to Peg-IFNa in JAK2V617F vs. CALR mutant MPN patients are due to JAK1-mediated STAT1 activation and autoregulation

Author

Czech, Julia, Cordua, Sabrina, Weinbergerova, Barbora, Han, Lijuan, Schubert, Claudia, Brümmendorf, Tim H., Mayer, Jiri, Racil, Zdenek, Kubesova, Blanka, Knudsen, Trine, Sørensen, Anders, Holmstrøm, Morten, Kjær, Lasse, Skov, Vibe, Larsen, Thomas Stauffer, Hasselbalch, Hans C., Chatain, Nicolas, and Koschmieder, Steffen

Published
2017

13. JAK2V617F but not CALR mutations confer increased molecular responses to interferon-α via JAK1/STAT1 activation

Author

Czech, Julia, primary, Cordua, Sabrina, additional, Weinbergerova, Barbora, additional, Baumeister, Julian, additional, Crepcia, Assja, additional, Han, Lijuan, additional, Maié, Tiago, additional, Costa, Ivan G., additional, Denecke, Bernd, additional, Maurer, Angela, additional, Schubert, Claudia, additional, Feldberg, Kristina, additional, Gezer, Deniz, additional, Brümmendorf, Tim H., additional, Müller-Newen, Gerhard, additional, Mayer, Jiri, additional, Racil, Zdenek, additional, Kubesova, Blanka, additional, Knudsen, Trine, additional, Sørensen, Anders L., additional, Holmström, Morten, additional, Kjær, Lasse, additional, Skov, Vibe, additional, Larsen, Thomas Stauffer, additional, Hasselbalch, Hans C., additional, Chatain, Nicolas, additional, and Koschmieder, Steffen, additional

Published
2018
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14. Thrombopoietin receptor is required for the oncogenic function of CALR mutants

Author

Nivarthi, Harini, Chen, Doris, Cleary, Ciara, Kubesova, Blanka, Jäger, Roland, Bogner, Edith, Marty, Caroline, Pecquet, Christian, Vainchenker , William, Constantinescu, Stefan N., Kralovics , Robert, and UCL - SSS/DDUV - Institut de Duve

Subjects
Mice, Cell Transformation, Neoplastic, Myeloproliferative Disorders, Animals, Humans, Calreticulin, Transcriptome, Receptors, Thrombopoietin, Letter to the Editor
Published
2016

15. Low-Burden TP53 Mutations Occur in Chronic Phase of Myeloproliferative Neoplasms Regardless of Hydroxyurea Administration, Disease Type, and JAK2 Status

Author

Kubesova, Blanka, primary, Pavlova, Sarka, additional, Malcikova, Jitka, additional, Kabathova, Jitka, additional, Radova, Lenka, additional, Tom, Nikola, additional, Tichy, Boris, additional, Plevova, Karla, additional, Kantorova, Barbara, additional, Fiedorova, Kristyna, additional, Kissova, Jarmila, additional, Gisslinger, Bettina, additional, Gisslinger, Heinz, additional, Mayer, Jiri, additional, Kralovics, Robert, additional, Pospisilova, Sarka, additional, and Doubek, Michael, additional

Published
2016
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16. Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms

Author

Milosevic Feenstra, Jelena D, Nivarthi, Harini, Gisslinger, Heinz, Leroy, Emilie, Rumi, Elisa, Chachoua, Ilyas, Bagienski, Klaudia, Kubesova, Blanka, Pietra, Daniela, Gisslinger, Bettina, Milanesi, Chiara, Jäger, Roland, Chen, Doris, Berg, Tiina, Schalling, Martin, Schuster, Michael, Bock, Christoph, Constantinescu, Stefan N., Cazzola, Mario, Kralovics, Robert, and UCL - SSS/DDUV - Institut de Duve

Subjects
Myeloproliferative Disorders, Myeloid Neoplasia, DNA Copy Number Variations, DNA Mutational Analysis, High-Throughput Nucleotide Sequencing, Genomics, Janus Kinase 2, Primary Myelofibrosis, X Chromosome Inactivation, Mutation, Humans, Exome, Receptors, Thrombopoietin, Thrombocythemia, Essential
Abstract

Essential thrombocythemia (ET) and primary myelofibrosis (PMF) are chronic diseases characterized by clonal hematopoiesis and hyperproliferation of terminally differentiated myeloid cells. The disease is driven by somatic mutations in exon 9 of CALR or exon 10 of MPL or JAK2-V617F in90% of the cases, whereas the remaining cases are termed "triple negative." We aimed to identify the disease-causing mutations in the triple-negative cases of ET and PMF by applying whole-exome sequencing (WES) on paired tumor and control samples from 8 patients. We found evidence of clonal hematopoiesis in 5 of 8 studied cases based on clonality analysis and presence of somatic genetic aberrations. WES identified somatic mutations in 3 of 8 cases. We did not detect any novel recurrent somatic mutations. In 3 patients with clonal hematopoiesis analyzed by WES, we identified a somatic MPL-S204P, a germline MPL-V285E mutation, and a germline JAK2-G571S variant. We performed Sanger sequencing of the entire coding region of MPL in 62, and of JAK2 in 49 additional triple-negative cases of ET or PMF. New somatic (T119I, S204F, E230G, Y591D) and 1 germline (R321W) MPL mutation were detected. All of the identified MPL mutations were gain-of-function when analyzed in functional assays. JAK2 variants were identified in 5 of 57 triple-negative cases analyzed by WES and Sanger sequencing combined. We could demonstrate that JAK2-V625F and JAK2-F556V are gain-of-function mutations. Our results suggest that triple-negative cases of ET and PMF do not represent a homogenous disease entity. Cases with polyclonal hematopoiesis might represent hereditary disorders.

Published
2015

17. Thrombopoietin receptor is required for the oncogenic function of CALR mutants

Author

UCL - SSS/DDUV - Institut de Duve, Nivarthi, Harini, Chen, Doris, Cleary, Ciara, Kubesova, Blanka, Jäger, Roland, Bogner, Edith, Marty, Caroline, Pecquet, Christian, Vainchenker , William, Constantinescu, Stefan N., Kralovics , Robert, UCL - SSS/DDUV - Institut de Duve, Nivarthi, Harini, Chen, Doris, Cleary, Ciara, Kubesova, Blanka, Jäger, Roland, Bogner, Edith, Marty, Caroline, Pecquet, Christian, Vainchenker , William, Constantinescu, Stefan N., and Kralovics , Robert

Published
2016

18. Whole exome sequencing identifies novel MPL and JAK2 mutations in triple negative myeloproliferative neoplasms.

Author

UCL - SSS/DDUV - Institut de Duve, Milosevic Feenstra, Jelena D, Nivarthi, Harini, Gisslinger, Heinz, Leroy, Emilie, Rumi, Elisa, Chachoua, Ilyas, Bagienski, Klaudia, Kubesova, Blanka, Pietra, Daniela, Gisslinger, Bettina, Milanesi, Chiara, Jäger, Roland, Chen, Doris, Berg, Tiina, Schalling, Martin, Schuster, Michael, Bock, Christoph, Constantinescu, Stefan N., Cazzola, Mario, Kralovics, Robert, UCL - SSS/DDUV - Institut de Duve, Milosevic Feenstra, Jelena D, Nivarthi, Harini, Gisslinger, Heinz, Leroy, Emilie, Rumi, Elisa, Chachoua, Ilyas, Bagienski, Klaudia, Kubesova, Blanka, Pietra, Daniela, Gisslinger, Bettina, Milanesi, Chiara, Jäger, Roland, Chen, Doris, Berg, Tiina, Schalling, Martin, Schuster, Michael, Bock, Christoph, Constantinescu, Stefan N., Cazzola, Mario, and Kralovics, Robert

Abstract

Essential thrombocythemia (ET) and primary myelofibrosis (PMF) are chronic diseases characterized by clonal hematopoiesis and hyperproliferation of terminally differentiated myeloid cells. The disease is driven by somatic mutations in exon 9 of CALR, exon 10 of MPL or JAK2-V617F in >90% of the cases, while the remaining cases are termed "triple negative". We aimed to identify the disease causing mutations in the triple negative cases of ET and PMF by applying whole exome sequencing (WES) on paired tumor and control samples from 8 patients. We found evidence of clonal hematopoiesis in 5/8 studied cases based on clonality analysis and presence of somatic genetic aberrations. WES identified somatic mutations in 3/8 cases. We did not detect any novel recurrent somatic mutations. In 3 patients with clonal hematopoiesis, analyzed by WES, we identified a somatic MPL-S204P and a germline MPL-V285E mutation, as well as a germline JAK2-G571S variant. Sequencing of entire coding region of MPL and JAK2 was performed in additional 62 and 49 triple negative cases of ET or PMF, respectively. We detected new somatic (T119I, S204F, E230G, Y591D) and one germline (R321W) MPL mutation in 5/62 cases. All the mutations were gain-of-function mutations when analyzed in functional assays. JAK2 variants were identified in 5/57 triple negative cases and 3 of them were germline. We could demonstrate that JAK2-V625F and JAK2-F556V are gain-of-function mutations. Our results suggest that triple negative cases of ET and PMF do not represent a homogenous disease entity. Cases with polyclonal hematopoiesis might represent hereditary disorders.

Published
2015

19. Whole Exome Sequencing Identifies Novel MPL and JAK2 M utations in Triple Negative Myeloproliferative Neoplasms

Author

Milosevic Feenstra, Jelena D, primary, Nivarthi, Harini, additional, Gisslinger, Heinz, additional, Leroy, Emilie, additional, Rumi, Elisa, additional, Chachoua, Ilyas, additional, Bagienski, Klaudia, additional, Kubesova, Blanka, additional, Pietra, Daniela, additional, Gisslinger, Bettina, additional, Jäger, Roland, additional, Chen, Doris, additional, Berg, Tiina, additional, Schalling, Martin, additional, Schuster, Michael, additional, Bock, Christoph, additional, Constantinescu, Stefan N., additional, Cazzola, Mario, additional, and Kralovics, Robert, additional

Published
2015
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21. Whole-exome sequencing identifies novel MPLand JAK2mutations in triple-negative myeloproliferative neoplasms

Author

Milosevic Feenstra, Jelena D., Nivarthi, Harini, Gisslinger, Heinz, Leroy, Emilie, Rumi, Elisa, Chachoua, Ilyas, Bagienski, Klaudia, Kubesova, Blanka, Pietra, Daniela, Gisslinger, Bettina, Milanesi, Chiara, Jäger, Roland, Chen, Doris, Berg, Tiina, Schalling, Martin, Schuster, Michael, Bock, Christoph, Constantinescu, Stefan N., Cazzola, Mario, and Kralovics, Robert

Abstract

Essential thrombocythemia (ET) and primary myelofibrosis (PMF) are chronic diseases characterized by clonal hematopoiesis and hyperproliferation of terminally differentiated myeloid cells. The disease is driven by somatic mutations in exon 9 of CALRor exon 10 of MPLor JAK2-V617F in >90% of the cases, whereas the remaining cases are termed “triple negative.” We aimed to identify the disease-causing mutations in the triple-negative cases of ET and PMF by applying whole-exome sequencing (WES) on paired tumor and control samples from 8 patients. We found evidence of clonal hematopoiesis in 5 of 8 studied cases based on clonality analysis and presence of somatic genetic aberrations. WES identified somatic mutations in 3 of 8 cases. We did not detect any novel recurrent somatic mutations. In 3 patients with clonal hematopoiesis analyzed by WES, we identified a somatic MPL-S204P, a germline MPL-V285E mutation, and a germline JAK2-G571S variant. We performed Sanger sequencing of the entire coding region of MPLin 62, and of JAK2in 49 additional triple-negative cases of ET or PMF. New somatic (T119I, S204F, E230G, Y591D) and 1 germline (R321W) MPLmutation were detected. All of the identified MPLmutations were gain-of-function when analyzed in functional assays. JAK2variants were identified in 5 of 57 triple-negative cases analyzed by WES and Sanger sequencing combined. We could demonstrate that JAK2-V625F and JAK2-F556V are gain-of-function mutations. Our results suggest that triple-negative cases of ET and PMF do not represent a homogenous disease entity. Cases with polyclonal hematopoiesis might represent hereditary disorders.

Published
2016
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22. Low-Burden TP53Mutations Occur in Chronic Phase of Myeloproliferative Neoplasms Regardless of Hydroxyurea Administration, Disease Type, and JAK2Status

Author

Kubesova, Blanka, Pavlova, Sarka, Malcikova, Jitka, Kabathova, Jitka, Radova, Lenka, Tom, Nikola, Tichy, Boris, Plevova, Karla, Kantorova, Barbara, Fiedorova, Kristyna, Kissova, Jarmila, Gisslinger, Bettina, Gisslinger, Heinz, Mayer, Jiri, Kralovics, Robert, Pospisilova, Sarka, and Doubek, Michael

Published
2016
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23. Whole Exome Sequencing Identifies Novel MPLand JAK2 Mutations in Triple Negative Myeloproliferative Neoplasms

Author

Milosevic Feenstra, Jelena D, Nivarthi, Harini, Gisslinger, Heinz, Leroy, Emilie, Rumi, Elisa, Chachoua, Ilyas, Bagienski, Klaudia, Kubesova, Blanka, Pietra, Daniela, Gisslinger, Bettina, Jäger, Roland, Chen, Doris, Berg, Tiina, Schalling, Martin, Schuster, Michael, Bock, Christoph, Constantinescu, Stefan N., Cazzola, Mario, and Kralovics, Robert

Abstract

Essential thrombocythemia (ET) and primary myelofibrosis (PMF) are chronic myeloproliferative neoplasms (MPN) characterized by clonal hematopoiesis and hyperproliferation of terminally differentiated myeloid cells. Most of the cases are sporadic and driven by somatic mutations, although familial clustering is observed. The most common mutation affecting 50-60% of the cases is JAK2-V617F, while 25-30% of the patients carry somatic mutations in exon 9 of CALR. MPLexon 10 mutations affect ~5% of the cases. JAK2, CALRand MPLmutations are mutually exclusive and account for >90% of ET and PMF cases. In 12% of ET and 5% of PMF cases the disease drivers remain unknown. These patients are termed as triple negative. The mutational analysis for diagnostic purposes is limited to exons 14 of JAK2, exon 10 of MPLand exon 9 of CALR. The aim of this study was to identify disease causing mutation in triple negative cases of ET and PMF.

Published
2015
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25. ATM mutations uniformly lead to ATM dysfunction in chronic lymphocytic leukemia: application of functional test using doxorubicin.

Author

Navrkalova V, Sebejova L, Zemanova J, Kminkova J, Kubesova B, Malcikova J, Mraz M, Smardova J, Pavlova S, Doubek M, Brychtova Y, Potesil D, Nemethova V, Mayer J, Pospisilova S, and Trbusek M

Subjects
Adult, Aged, Aged, 80 and over, Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors, Ataxia Telangiectasia Mutated Proteins physiology, Cell Survival physiology, Chromosome Deletion, Chromosomes, Human, Pair 11 genetics, Cohort Studies, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear pathology, Male, Middle Aged, Retrospective Studies, Ataxia Telangiectasia Mutated Proteins genetics, Cell Survival drug effects, Doxorubicin pharmacology, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Mutation genetics
Abstract

ATM abnormalities are frequent in chronic lymphocytic leukemia and represent an important prognostic factor. Sole 11q deletion does not result in ATM inactivation by contrast to biallelic defects involving mutations. Therefore, the analysis of ATM mutations and their functional impact is crucial. In this study, we analyzed ATM mutations in predominantly high-risk patients using: i) resequencing microarray and direct sequencing; ii) Western blot for total ATM level; iii) functional test based on p21 gene induction after parallel treatment of leukemic cells with fludarabine and doxorubicin. ATM dysfunction leads to impaired p21 induction after doxorubicin exposure. We detected ATM mutation in 16% (22 of 140) of patients, and all mutated samples manifested demonstrable ATM defect (impaired p21 upregulation after doxorubicin and/or null protein level). Loss of ATM function in mutated samples was also evidenced through defective p53 pathway activation after ionizing radiation exposure. ATM mutation frequency was 34% in patients with 11q deletion, 4% in the TP53-defected group, and 8% in wild-type patients. Our functional test, convenient for routine use, showed high sensitivity (80%) and specificity (97%) for ATM mutations prediction. Only cells with ATM mutation, but not those with sole 11q deletion, were resistant to doxorubicin. As far as fludarabine is concerned, this difference was not observed. Interestingly, patients from both these groups experienced nearly identical time to first treatment. In conclusion, ATM mutations either alone or in combination with 11q deletion uniformly led to demonstrable ATM dysfunction in patients with chronic lymphocytic leukemia and mutation presence can be predicted by the functional test using doxorubicin.

Published
2013
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