47 results on '"Kotaskova J"'
Search Results
2. GENOMIC ABERRATIONS DETECTED IN CIRCULATING TUMOR DNA FROM CEREBROSPINAL FLUID AND PLASMA OF PATIENTS WITH PRIMARY AND SECONDARY CNS LYMPHOMAS WITH NEGATIVE FLOWCYTOMETRY
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Mareckova, A., primary, Navrkalova, V., additional, Bohunova, M., additional, Hrabcakova, V., additional, Hricko, S., additional, Reigl, T., additional, Porc, J., additional, Janikova, A., additional, and Kotaskova, J., additional
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- 2023
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3. Multiple productive IGH rearrangements denote oligoclonality even in immunophenotypically monoclonal CLL
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Brazdilova, K, Plevova, K, Francova, Skuhrova H, Kockova, H, Borsky, M, Bikos, V, Malcikova, J, Oltova, A, Kotaskova, J, Tichy, B, Brychtova, Y, Mayer, J, Doubek, M, and Pospisilova, S
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- 2018
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4. P614: SUBCLONAL ARCHITECTURE OF CHROMOSOMES REVEALED BY SINGLE-CELL ANALYSIS OF GENE EXPRESSION IN A PATIENT WITH CLONAL EVOLUTION OF RELAPSING/REFRACTORY CLL
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Kotaskova, J., primary, Kurucova, T., additional, Reblova, K., additional, Valisova, M., additional, Zavacka, K., additional, Mareckova, A., additional, Bohunova, M., additional, Pavlova, S., additional, Malcikova, J., additional, Navrkalova, V., additional, Jarosova, M., additional, Doubek, M., additional, Plevova, K., additional, and Pospisilova, S., additional
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- 2022
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5. P608: DISTINCT P53 PHOSPHORYLATION PATTERNS IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS ARE REFLECTED IN CIRCUMJACENT PATHWAYS’ ACTIVATION UPON DNA DAMAGE
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Pesova, M., primary, Mancikova, V., additional, Helma, R., additional, Pavlova, S., additional, Hejret, V., additional, Taus, P., additional, Hynst, J., additional, Plevova, K., additional, Kotaskova, J., additional, Malcikova, J., additional, and Pospisilova, S., additional
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- 2022
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6. P620: DYNAMICS OF GENOMIC ABERRATIONS IN RELATION TO DISEASE ACTIVITY IN UNTREATED PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA
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Navrkalova, V., primary, Kotaskova, J., additional, Plevova, K., additional, Reigl, T., additional, Valisova, M., additional, Bohunova, M., additional, Zenatova, M., additional, Radova, L., additional, Panovska, A., additional, and Pospisilova, S., additional
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- 2022
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7. Memory B-cell like chronic lymphocytic leukaemia is associated with specific methylation profile of WNT5A promoter and undetectable expression of WNT5A gene
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Poppova, L, Pavlova, S, Gonzalez, B, Kotaskova, J, Plevova, K, Dumbovic, G, Janovska, P, Bystry, V, Panovska, A, Bezdekova, L, Maslejova, S, Brychtova, Y, Doubek, M, Krzyzankova, M, Borsky, M, Mayer, J, Bryja, V, Alonso, S, and Pospisilova, S
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m-CLL ,methylation ,WNT5A ,i-CLL ,chronic lymphocytic leukaemia - Abstract
Genome methylation profiles define naive-like (n-CLL), memory-like (m-CLL), and intermediate (i-CLL) subsets of chronic lymphocytic leukaemia (CLL). The profiles can be easily determined by the analysis of the five-CpG signature. m-CLL, i-CLL, and n-CLL with the good, intermediate, and poor prognoses, respectively, differ by the somatic hypermutation status of the immunoglobulin heavy chain variable gene (IGHV), a widely used prognostic predictor in CLL. We have previously shown that the expression of WNT5A, encoding a ROR1 ligand, distinguishes patients with the worse outcome within the prognostically favourable IGHV-mutated subgroup. To analyse the mechanisms controlling WNT5A expression, we investigated the methylation status of 54 CpG sites within the WNT5A promoter and its relation to the WNT5A gene expression. In a cohort of 59 CLL patients balanced for combinations of IGHV and WNT5A statuses, we identified three promoter CpG sites whose methylation level correlated with the WNT5A expression within the IGHV-mutated subgroup. Further, we complemented our data with the methylation status of the five-CpG signature. IGHV-mutated/WNT5A-negative and IGHV-mutated/WNT5A-positive cases overlapped with m-CLL and i-CLL methylation subgroups, respectively, while most IGHV-unmutated samples were assigned to n-CLL. Median methylation levels of all the three CpG sites in the WNT5A promoter were lowest in i-CLL. Finally, a detailed analysis of m-CLL and i-CLL showed that undetectable WNT5A expression predicts longer treatment-free survival with higher statistical significance than the classification according to the five-CpG signature. To conclude, a favourable m-CLL subgroup is associated with mutated IGHV and undetectable WNT5A expression due to its promoter methylation.
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- 2022
8. miR-34a, miR-29c and miR-17-5p are downregulated in CLL patients with TP53 abnormalities
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Mraz, M, Malinova, K, Kotaskova, J, Pavlova, S, Tichy, B, Malcikova, J, Stano Kozubik, K, Smardova, J, Brychtova, Y, Doubek, M, Trbusek, M, Mayer, J, and Pospisilova, S
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- 2009
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9. Identification of somatic hypermutations in the TP53 gene in B-cell chronic lymphocytic leukemia
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Malcikova, J., Smardova, J., Pekova, S., Cejkova, S., Kotaskova, J., Tichy, B., Francova, H., Doubek, M., Brychtova, Y., Janek, D., Pospisilova, S., Mayer, J., Dvorakova, D., and Trbusek, M.
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- 2008
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10. INTERNATIONAL PROGNOSTIC SCORE FOR EARLY STAGE CHRONIC LYMPHOCYTIC LEUKEMIA (IPS-A)
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Condoluci, A., primary, Terzi di Bergamo, L., additional, Langerbeins, P., additional, Hoechstetter, M., additional, Herling, C., additional, De Paoli, L., additional, Delgado, J., additional, Gentile, M., additional, Doubek, M., additional, Mauro, F.R., additional, Chiodin, G., additional, Mattsson, M., additional, Bahlo, J., additional, Cutrona, G., additional, Kotaskova, J., additional, Deambrogi, C., additional, Moia, R., additional, Gerber, B., additional, Zucca, E., additional, Ghielmini, M., additional, Cavalli, F., additional, Stüssi, G., additional, Neri, A., additional, Ferrarini, M., additional, Rosenquist, R., additional, Forconi, F., additional, Foà, R., additional, Pospisilova, S., additional, Morabito, F., additional, Wierda, W.G., additional, Montserrat, E., additional, Gaidano, G., additional, Hallek, M., additional, and Rossi, D., additional
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- 2019
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11. Development of 'Intelligence': A Reinterpretation by Means of Guttman's Smallest Space Analysis
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Johnson, J. and Kotásková, J.
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- 1969
12. Whole-exome sequencing in relapsing chronic lymphocytic leukemia: Clinical impact of recurrent RPS15 mutations
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Ljungström, V. Cortese, D. Young, E. Pandzic, T. Mansouri, L. Plevova, K. Ntoufa, S. Baliakas, P. Clifford, R. Sutton, L.-A. Blakemore, S.J. Stavroyianni, N. Agathangelidis, A. Rossi, D. Höglund, M. Kotaskova, J. Juliusson, G. Belessi, C. Chiorazzi, N. Panagiotidis, P. Langerak, A.W. Smedby, K.E. Oscier, D. Gaidano, G. Schuh, A. Davi, F. Pott, C. Strefford, J.C. Trentin, L. Pospisilova, S. Ghia, P. Stamatopoulos, K. Sjöblom, T. Rosenquist, R.
- Abstract
Fludarabine, cyclophosphamide, and rituximab (FCR) is first-line treatment of medically fit chronic lymphocytic leukemia (CLL) patients; however, despite good response rates, many patients eventually relapse. Although recent high-throughput studies have identified novel recurrent genetic lesions in adverse prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, and BIRC3), a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases, selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal before treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid, evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared with wild-type RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology. © 2016 by The American Society of Hematology.
- Published
- 2016
13. Multiple productive IGH rearrangements denote oligoclonality even in immunophenotypically monoclonal CLL
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Brazdilova, K, primary, Plevova, K, additional, Skuhrova Francova, H, additional, Kockova, H, additional, Borsky, M, additional, Bikos, V, additional, Malcikova, J, additional, Oltova, A, additional, Kotaskova, J, additional, Tichy, B, additional, Brychtova, Y, additional, Mayer, J, additional, Doubek, M, additional, and Pospisilova, S, additional
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- 2017
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14. EARLY SEX DIFFERENCES AS INDICATORS OF GENETIC INFLUENCES IN SOCIALIZATION
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Kotaskova, J., primary
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- 1972
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15. Hyperfamiliarity in patients with temporal lobe epilepsy
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Kotaskova, J., primary, Cavanna, A.E., additional, Bradac, O., additional, Javurkova, A., additional, and Marusic, P., additional
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- 2013
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16. Postoperative changes in emotional recognition and social cognition in temporal lobe epilepsy patients
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Marusic, P., primary, Kotaskova, J., additional, and Javurkova, A., additional
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- 2013
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17. 67. Social cognition in temporal lobe epilepsy patients
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Kotaskova, J., primary, Marusic, P., additional, Kajukova, B., additional, and Javurkova, A., additional
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- 2010
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18. 13. Postoperative changes in emotional recognition and social cognition in TLE patients
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Marusic, P., primary, Kotaskova, J., additional, Kajukova, B., additional, and Javurkova, A., additional
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- 2010
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19. REFINING PROGNOSIS OF CHRONIC LYMPHOCYTIC LEUKEMIA WITH SOMATICALLY HYPERMUTATED B-CELL RECEPTORS: A NOVEL PROGNOSTIC INDEX ON BEHALF OF THE EUROPEAN RESEARCH INITIATIVE ON CLL (ERIC)
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Baliakas, P., Hadzidimitriou, A., Mattsson, M., Xochelli, A., Sutton, L. A., Minga, E., Scarfo, L., Rossi, D., Davis, Z., Agathangelidis, A., Villamor, N., Parker, H., Kotaskova, J., Stalika, E., Plevova, K., Mansouri, L., Cortese, D., Navarro Lopez, A., Delgado, J., Larrayoz, M., Anagnostopoulos, A., Belessi, C., Smedby, K. E., Juliusson, G., Strefford, J. C., Sarka Pospisilova, Oscier, D., Gaidano, G., Campo, E., Ghia, P., Rosenquist, R., and Stamatopoulos, K.
20. BIALLELIC TP53 GENE MUTATIONS DUE TO COPY-NEUTRAL LOSS OF HETEROZYGOSITY AND MONOALLELIC MUTATIONS IN ABSENCE OF 17P DELETION OCCUR IN CLL WITH COMPARABLE FREQUENCY
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Plevova, K., Malcikova, J., Sarka Pavlova, Kotaskova, J., Poppova, L., Smardova, J., Diviskova, E., Durechova, K., Oltova, A., Brychtova, Y., Panovska, A., Doubek, M., and Pospisilova, S.
21. TREATMENT WITH BCR INHIBITORS INCREASES ROR1 EXPRESSION IN CLL CELLS
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Kotaskova, J., Pavlova, S., Plevova, K., Malcikova, J., Stehlikova, O., Poppova, L., Kockova, H., Doubek, M., Bryja, V., and Sarka Pospisilova
22. MICRORNAS EXPRESSION PATTERN IN AGGRESSIVE SUBTYPE OF CHRONIC LYMPHOCYTIC LEUKEMIA
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Mraz, M., Malinova, K., Kotaskova, J., Pavlova, S., Tichy, B., Malcikova, J., Lochmanova, J., Brychtova, Y., Trbusek, M., Mayer, J., and Sarka Pospisilova
23. DECREASED EXPRESSION OF WNT3, A CANONICAL WNT PATHWAY LIGAND, IS FREQUENT IN CHRONIC LYMPHOCYTIC LEUKEMIA PROGRESSION AND IDENTIFIES PATIENTS WITH SHORT TREATMENT-FREE SURVIVAL IN MUTATED IGHV SUBSET
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Poppova, L., Janovska, P., Plevova, K., Radova, L., Plesingerova, H., Borsky, M., Kotaskova, J., Kantorova, B., Hlozkova, M., Figulova, J., Brychtova, Y., Doubek, M., Kozubik, A., Pospisilova, S., Sarka Pavlova, and Bryja, V.
24. 13Q DELETION IS PREDOMINANT CYTOGENETIC ABERRATION NEWLY AQUIRED DURING CHRONIC LYMPHOCYTIC LEUKEMIA COURSE IRRESPECTIVE OF DISEASE ACTIVITY AND TREATMENT STATUS
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Kotaskova, J., Malcikova, J., Diviskova, E., Pavlova, S., Mejstrikova, S., Vranova, V., Plevova, K., Plesingerova, H., Doubek, M., Mayer, J., and Sarka Pospisilova
25. Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations
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Larry Mansouri, Anton W. Langerak, Anna Schuh, Tatjana Pandzic, Martin Höglund, Lesley-Ann Sutton, David Oscier, Stuart Blakemore, Karla Plevová, Christiane Pott, Karin E. Smedby, Emma Young, R Clifford, Andreas Agathangelidis, Livio Trentin, Davide Rossi, Viktor Ljungström, Jonathan C. Strefford, Panagiotis Panagiotidis, Jana Kotašková, Šárka Pospíšilová, Paolo Ghia, Tobias Sjöblom, Kostas Stamatopoulos, Stavroula Ntoufa, Niki Stavroyianni, Diego Cortese, Richard Rosenquist, Gianluca Gaidano, Nicholas Chiorazzi, Gunnar Juliusson, Frederic Davi, Panagiotis Baliakas, Chrysoula Belessi, Immunology, Ljungström, V, Cortese, D, Young, E, Pandzic, T, Mansouri, L, Plevova, K, Ntoufa, S, Baliakas, P, Clifford, R, Sutton, La, Blakemore, S, Stavroyianni, N, Agathangelidis, A, Rossi, D, Höglund, M, Kotaskova, J, Juliusson, G, Belessi, C, Chiorazzi, N, Panagiotidis, P, Langerak, Aw, Smedby, Ke, Oscier, D, Gaidano, G, Schuh, A, Davi, F, Pott, C, Strefford, Jc, Trentin, L, Pospisilova, S, Ghia, PAOLO PROSPERO, Stamatopoulos, K, Sjöblom, T, and Rosenquist, R.
- Subjects
Ribosomal Proteins ,0301 basic medicine ,medicine.medical_specialty ,Chronic lymphocytic leukemia ,Blotting, Western ,DNA Mutational Analysis ,Immunology ,Mutation, Missense ,Cell Separation ,Kaplan-Meier Estimate ,Biology ,Transfection ,medicine.disease_cause ,Biochemistry ,Somatic evolution in cancer ,03 medical and health sciences ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Immunoprecipitation ,Exome ,Cyclophosphamide ,Exome sequencing ,Mutation ,Lymphoid Neoplasia ,Hematology ,Cell Biology ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,NFKBIE ,3. Good health ,Fludarabine ,030104 developmental biology ,Drug Resistance, Neoplasm ,Cancer research ,Neoplasm Recurrence, Local ,Tumor Suppressor Protein p53 ,Rituximab ,Vidarabine ,medicine.drug - Abstract
Fludarabine, cyclophosphamide, and rituximab (FCR) is first-line treatment of medically fit chronic lymphocytic leukemia (CLL) patients; however, despite good response rates, many patients eventually relapse. Although recent high-throughput studies have identified novel recurrent genetic lesions in adverse prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, and BIRC3), a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases, selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal before treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid, evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared with wild-type RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology.
- Published
- 2016
26. Unveiling the dynamics and molecular landscape of a rare chronic lymphocytic leukemia subpopulation driving refractoriness: insights from single-cell RNA sequencing.
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Kurucova T, Reblova K, Janovska P, Porc JP, Navrkalova V, Pavlova S, Malcikova J, Plevova K, Tichy B, Doubek M, Bryja V, Kotaskova J, and Pospisilova S
- Abstract
Early identification of resistant cancer cells is currently a major challenge, as their expansion leads to refractoriness. To capture the dynamics of these cells, we made a comprehensive analysis of disease progression and treatment response in a chronic lymphocytic leukemia (CLL) patient using a combination of single-cell and bulk genomic methods. At diagnosis, the patient presented with unfavorable genetic markers, including notch receptor 1 (NOTCH1) mutation and loss(11q). The initial and subsequent treatment lines did not lead to a durable response and the patient developed refractory disease. Refractory CLL cells featured substantial dysregulation in B-cell phenotypic markers such as human leukocyte antigen (HLA) genes, immunoglobulin (IG) genes, CD19 molecule (CD19), membrane spanning 4-domains A1 (MS4A1; previously known as CD20), CD79a molecule (CD79A) and paired box 5 (PAX5), indicating B-cell de-differentiation and disease transformation. We described the clonal evolution and characterized in detail two cell populations that emerged during the refractory disease phase, differing in the presence of high genomic complexity. In addition, we successfully tracked the cells with high genomic complexity back to the time before treatment, where they formed a rare subpopulation. We have confirmed that single-cell RNA sequencing enables the characterization of refractory cells and the monitoring of their development over time., (© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
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- 2024
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27. Integrative NGS testing reveals clonal dynamics of adverse genomic defects contributing to a natural progression in treatment-naïve CLL patients.
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Navrkalova V, Plevova K, Radova L, Porc J, Pal K, Malcikova J, Pavlova S, Doubek M, Panovska A, Kotaskova J, and Pospisilova S
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- Humans, Prognosis, Mutation, Genomics, High-Throughput Nucleotide Sequencing, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Abstract
Large-scale next-generation sequencing (NGS) studies revealed extensive genetic heterogeneity, driving a highly variable clinical course of chronic lymphocytic leukaemia (CLL). The evolution of subclonal populations contributes to diverse therapy responses and disease refractoriness. Besides, the dynamics and impact of subpopulations before therapy initiation are not well understood. We examined changes in genomic defects in serial samples of 100 untreated CLL patients, spanning from indolent to aggressive disease. A comprehensive NGS panel LYNX, which provides targeted mutational analysis and genome-wide chromosomal defect assessment, was employed. We observed dynamic changes in the composition and/or proportion of genomic aberrations in most patients (62%). Clonal evolution of gene variants prevailed over the chromosomal alterations. Unsupervised clustering based on aberration dynamics revealed four groups of patients with different clinical behaviour. An adverse cluster was associated with fast progression and early therapy need, characterized by the expansion of TP53 defects, ATM mutations, and 18p- alongside dynamic SF3B1 mutations. Our results show that clonal evolution is active even without therapy pressure and that repeated genetic testing can be clinically relevant during long-term patient monitoring. Moreover, integrative NGS testing contributes to the consolidated evaluation of results and accurate assessment of individual patient prognosis., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2024
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28. Other malignancies in the history of CLL: an international multicenter study conducted by ERIC, the European Research Initiative on CLL, in HARMONY.
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Chatzikonstantinou T, Scarfò L, Karakatsoulis G, Minga E, Chamou D, Iacoboni G, Kotaskova J, Demosthenous C, Smolej L, Mulligan S, Alcoceba M, Al-Shemari S, Aurran-Schleinitz T, Bacchiarri F, Bellido M, Bijou F, Calleja A, Medina A, Khan MA, Cassin R, Chatzileontiadou S, Collado R, Christian A, Davis Z, Dimou M, Donaldson D, Santos GD, Dreta B, Efstathopoulou M, El-Ashwah S, Enrico A, Fresa A, Galimberti S, Galitzia A, García-Serra R, Gimeno E, González-Gascón-Y-Marín I, Gozzetti A, Guarente V, Guieze R, Gogia A, Gupta R, Harrop S, Hatzimichael E, Herishanu Y, Hernández-Rivas JÁ, Inchiappa L, Jaksic O, Janssen S, Kalicińska E, Laribi K, Karakus V, Kater AP, Kho B, Kislova M, Konstantinou E, Koren-Michowitz M, Kotsianidis I, Kreitman RJ, Labrador J, Lad D, Levin MD, Levy I, Longval T, Lopez-Garcia A, Marquet J, Martin-Rodríguez L, Maynadié M, Maslejova S, Mayor-Bastida C, Mihaljevic B, Milosevic I, Miras F, Moia R, Morawska M, Murru R, Nath UK, Navarro-Bailón A, Oliveira AC, Olivieri J, Oscier D, Panovska-Stavridis I, Papaioannou M, Papajík T, Kubova Z, Phumphukhieo P, Pierie C, Puiggros A, Rani L, Reda G, Rigolin GM, Ruchlemer R, Daniel de Deus Santos M, Schipani M, Schiwitza A, Shen Y, Simkovic M, Smirnova S, Abdelrahman Soliman DS, Spacek M, Tadmor T, Tomic K, Tse E, Vassilakopoulos T, Visentin A, Vitale C, von Tresckow J, Vrachiolias G, Vukovic V, Walewska R, Wasik-Szczepanek E, Xu Z, Yagci M, Yañez L, Yassin M, Zuchnicka J, Angelopoulou M, Antic D, Biderman B, Catherwood M, Claus R, Coscia M, Cuneo A, Demirkan F, Espinet B, Gaidano G, Kalashnikova OB, Laurenti L, Nikitin E, Pangalis GA, Panagiotidis P, Popov VM, Pospisilova S, Sportoletti P, Stavroyianni N, Tam C, Trentin L, Chatzidimitriou A, Bosch F, Doubek M, Ghia P, and Stamatopoulos K
- Abstract
Background: Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk factors and CLL-directed treatment is still unclear and represents the focus of this work., Methods: We conducted a retrospective international multicenter study to assess the incidence of OMs and detect potential risk factors in 19,705 patients with CLL, small lymphocytic lymphoma, or high-count CLL-like monoclonal B-cell lymphocytosis, diagnosed between 2000 and 2016. Data collection took place between October 2020 and March 2022., Findings: In 129,254 years of follow-up after CLL diagnosis, 3513 OMs were diagnosed (27.2 OMs/1000 person-years). The most common hematological OMs were Richter transformation, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Non-melanoma skin (NMSC) and prostate cancers were the most common solid tumors (STs).The only predictor for MDS and AML development was treatment with fludarabine and cyclophosphamide with/without rituximab (FC ± R) (OR = 3.7; 95% CI = 2.79-4.91; p < 0.001). STs were more frequent in males and patients with unmutated immunoglobulin heavy variable genes (OR = 1.77; 95% CI = 1.49-2.11; p < 0.001/OR = 1.89; 95% CI = 1.6-2.24; p < 0.001).CLL-directed treatment was associated with non-melanoma skin and prostate cancers (OR = 1.8; 95% CI = 1.36-2.41; p < 0.001/OR = 2.11; 95% CI = 1.12-3.97; p = 0.021). In contrast, breast cancers were more frequent in untreated patients (OR = 0.17; 95% CI = 0.08-0.33; p < 0.001).Patients with CLL and an OM had inferior overall survival (OS) than those without. AML and MDS conferred the worst OS (p < 0.001)., Interpretation: OMs in CLL impact on OS. Treatment for CLL increased the risk for AML/MDS, prostate cancer, and NMSC. FCR was associated with increased risk for AML/MDS., Funding: AbbVie, and EU/EFPIAInnovative Medicines Initiative Joint Undertaking HARMONY grant n° 116026., Competing Interests: TC received honoraria from AbbVie. LS received consulting fees from AbbVie, BeiGene, AstraZeneca, Lilly, and Janssen, honoraria from Janssen and Octapharma, support for attending meetings from BeiGene and Janssen and advisory board fees from Merck. SMu received advisory board fees from AbbVie, AstraZeneca, Janssen, Roche and BeiGene. JAHR received honoraria as a consultant from Janssen, AbbVie, AstraZeneca, Lilly, and BeiGene and support for attending meetings from Janssen, AbbVie, AstraZeneca, and BeiGene. LI received honoraria from AbbVie, Roche, and Janssen-Cilag. APK received advisory board fees and research money from Janssen, AbbVie, BMS, AstraZeneca, Roche/Genentech, support for attending meetings from Janssen and AbbVie. M-DL received travel expenses from Janssen and AbbVie. GMR received honoraria for participation to speaker's bureau from AbbVie, Astra Zeneca, Beigene, and Janssen, and support for attending meetings from Janssen. JVT received consulting fees from AbbVie, AstraZeneca, BeiGene, and Janssen, honoraria for scientific talks from AbbVie, AstraZeneca, BeiGene, Janssen, Lilly, and Roche, travel support from AbbVie, AstraZeneca, BeiGene, Janssen, Roche, and Lilly, and advisory boards fees for AbbVie, Amgen, AstraZeneca, BeiGene. GI received honoraria from Novartis, BMS, Sandoz, AstraZeneca, Janssen, Kite/Gilead, and Miltenyi, support for attending meetings from Kite/Gilead, AstraZeneca, and AbbVie and advisory board fees from Kite/Gilead, Novartis, BMS, and Autolus. FBi received support for attending meetings from AbbVie. RCo received support for attending meetings from Janssen-Cilag and S.A. SG received honoraria support for attending meetings from AbbVie, AstraZeneca, Jazz, Novartis, and Incyte, honoraria from Roche, Celgene, Pfizer, and Janssen, and support for attending meetings from Jazz, AstraZeneca, and Roche. RGS received support for attending meetings from AbbVie and S.L.U. RG received honoraria, consulting fees, and support for attending meetings from AbbVie, Beigene, Roche, Janssen, AstraZeneca. YH received honoraria from Janssen, AbbVie, Roche, AstraZeneca, Medion, and Lilly. OJ received honoraria from Johnson and Johnson, AstraZeneca, and Lilly, honoraria from Johnson and Johnson, AbbVie, AstraZeneca, and Lilly, and support for attending meetings from Johnson and Johnson, and AbbVie. LK received consulting fees from AbbVie, AstraZeneca, Janssen, Beigene, Takeda, and Novartis. MKM received honoraria from Novartis, Pfizer, and Gad Medical LTD and support for attending meetings from Novartis. IKo received honoraria and consulting fees from AbbVie and Janssen. IM received honoraria from AbbVie, Roche, Sandoz, AstraZeneca, and Janssen, and support for attending meetings from AbbVie, Roche, and Takeda. ANB received honoraria, advisory board fees and support for attending meetings from AbbVie, AstraZeneca, Takeda, Janssen, and Beigene. JO received honoraria from AbbVie, AstraZeneca, and Janssen. GR received consulting fees from AbbVie, AstraZeneca, Janssen, and Beigene, and is currently employed by AstraZeneca. TP received honoraria and advisory board fees from AbbVie, Janssen-Cilag, and AstraZeneca and support for attending meeting from AstraZeneca. MS received honoraria and support for attending meeting from AstraZeneca, AbbVie, and Janssen-Cilag and owns shares of stock in AbbVie, AstraZeneca, Merck, Eli Lilly, Sanofi, Johnson and Johnson, Pfizer, Gilead, and GSK. MSp received honoraria and consulting and advisory board fees, and support for attending meeting from AbbVie, AstraZeneca, and Janssen. ET received support for attending meetings from Takeda. TV received honoraria from Takeda, Roche, Genesis Pharma, Merck, Novartis, Gilead, Sandoz, AstraZeneca, Integris, and Servier and support for attending meetings from Takeda, Roche, Genesis Pharma, Merck, Pfizer, and Winmedica. CV received honoraria from AbbVie, consulting fees from AstraZeneca and support for attending meeting from AstraZeneca, Takeda, and Janssen. RW received honoraria from AbbVie, AstraZeneca, and Beigene, support for attending meetings from Janssen, AbbVie, and AstraZeneca and advisory board fees from AbbVie, AstraZeneca, Janssen, Beigene, and SecuraBio. EWS received honoraria from AbbVie, Roche, and Janssen-Cilag and support for attending meetings from AbbVie. LY received honoraria from AbbVie, AstraZeneca, Novartis, Gilead, Janssen, Jazz, MSD, and Pfizer, support for attending meetings from AbbVie, AstraZeneca, Gilead, Janssen, and Pfizer, and advisory board fees from AbbVie, AstraZeneca, Jazz, Janssen, Beigene, and Celgene. MAn received consulting fees from AbbVie, Takeda, Janssen, Roche, Genesis, Gilead, and Amgen and honoraria from AbbVie, Takeda, Roche, Genesis, Gilead, and Novartis. MC received honoraria, advisory board fees, and support for attending meetings from AbbVie, AstraZeneca, and Janssen. ACu received honoraria, advisory board fees, and support for attending meetings from AbbVie, AstraZeneca, Beigene, Janssen, and Lilly. FD support for attending meetings from Janssen and AbbVie. GG received honoraria, and advisory board fees from AbbVie, AstraZeneca, Beigene, Janssen and advisory board fees from Lilly. EN received honoraria from AbbVie. LSm received consulting fees, honoraria and support for attending meetings from AbbVie, AstraZeneca, and Janssen and advisory board fees from AbbVie and AstraZeneca. NS received honoraria from Janssen, AbbVie, AstraZeneca, and Lilly, and support for attending meetings from Janssen and AstraZeneca. CT received honoraria from AbbVie, Beigene, Janssen, and LOXO. FB received consulting fees, honoraria and payment for expert testimony from AbbVie, Genentech, Novartis, Takeda, Janssen, Roche, Mundipharma, Celgene/BMS, AstraZeneca, Lilly, Beigene, Gilead and TG Therapeutics, Advantage Allogene, Lava Therapeutics, and Enterome. MDo received honoraria and advisory board fees from AbbVie, AstraZeneca and Janssen, advisory board fees from Swixx, and support for attending meetings from Janssen. PG received honoraria and consulting fees from AbbVie, AstraZeneca, BMS, Janssen, Lilly/Loxo Oncology, MSD, and Roche; grant support from AbbVie, AstraZeneca, BMS, Janssen. KS received honoraria from Janssen, AbbVie, Lilly and AstraZeneca, consulting fees and support for attending meetings from Janssen and AstraZeneca. GK, EM, DC, JK, CD, MA, SA, TAS, FBa, MB, ACa, AM, AKM, RC, SC, ACh, ZD, MDi, DD, GDS, BD, ME, SEA, AE, AF, AG, EG, IGGM, AGo, AjG, RGu, SH, EH, SJ, EKa, VK, BK, MK, EK, RJK, JL, DL, IL, TL, ALG, JM, LMR, MMa, SM, CMB, BM, FM, RM, MMo, RMu, UKN, ACO, DO, IPS, MP, ZK, PP, CP, AP, LR, RR, MDDS, AS, YS, MSi, SS, DSAS, TT, KT, AV, GV, VV, ZX, MYa, MY, JZ, DA, BB, MCa, RCl, BE, OBK, LL, GP, PPa, VMP, SP, PS, LT, AC, have no conflict of interest to disclose., (© 2023 Published by Elsevier Ltd.)
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- 2023
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29. Correction: Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY.
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Mansouri L, Thorvaldsdottir B, Sutton LA, Karakatsoulis G, Meggendorfer M, Parker H, Nadeu F, Brieghel C, Laidou S, Moia R, Rossi D, Catherwood M, Kotaskova J, Delgado J, Rodríguez-Vicente AE, Benito R, Rigolin GM, Bonfiglio S, Scarfo L, Mattsson M, Davis Z, Gogia A, Rani L, Baliakas P, Foroughi-Asl H, Jylhä C, Skaftason A, Rapado I, Miras F, Martinez-Lopez J, de la Serna J, Rivas JMH, Thornton P, Larráyoz MJ, Calasanz MJ, Fésüs V, Mátrai Z, Bödör C, Smedby KE, Espinet B, Puiggros A, Gupta R, Bullinger L, Bosch F, Tazón-Vega B, Baran-Marszak F, Oscier D, Nguyen-Khac F, Zenz T, Terol MJ, Cuneo A, Hernández-Sánchez M, Pospisilova S, Mills K, Gaidano G, Niemann CU, Campo E, Strefford JC, Ghia P, Stamatopoulos K, and Rosenquist R
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- 2023
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30. Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY.
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Mansouri L, Thorvaldsdottir B, Sutton LA, Karakatsoulis G, Meggendorfer M, Parker H, Nadeu F, Brieghel C, Laidou S, Moia R, Rossi D, Catherwood M, Kotaskova J, Delgado J, Rodríguez-Vicente AE, Benito R, Rigolin GM, Bonfiglio S, Scarfo L, Mattsson M, Davis Z, Gogia A, Rani L, Baliakas P, Foroughi-Asl H, Jylhä C, Skaftason A, Rapado I, Miras F, Martinez-Lopez J, de la Serna J, Rivas JMH, Thornton P, Larráyoz MJ, Calasanz MJ, Fésüs V, Mátrai Z, Bödör C, Smedby KE, Espinet B, Puiggros A, Gupta R, Bullinger L, Bosch F, Tazón-Vega B, Baran-Marszak F, Oscier D, Nguyen-Khac F, Zenz T, Terol MJ, Cuneo A, Hernández-Sánchez M, Pospisilova S, Mills K, Gaidano G, Niemann CU, Campo E, Strefford JC, Ghia P, Stamatopoulos K, and Rosenquist R
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- Humans, Prognosis, Myeloid Differentiation Factor 88 genetics, Mutation, Phenotype, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3-9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management., (© 2022. The Author(s).)
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- 2023
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31. Memory B-cell like chronic lymphocytic leukaemia is associated with specific methylation profile of WNT5A promoter and undetectable expression of WNT5A gene.
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Poppova L, Pavlova S, Gonzalez B, Kotaskova J, Plevova K, Dumbovic G, Janovska P, Bystry V, Panovska A, Bezdekova L, Maslejova S, Brychtova Y, Doubek M, Krzyzankova M, Borsky M, Mayer J, Bryja V, Alonso S, and Pospisilova S
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- Humans, Immunoglobulin Heavy Chains genetics, Immunoglobulin Heavy Chains metabolism, Ligands, DNA Methylation, Promoter Regions, Genetic, Prognosis, Mutation, Wnt-5a Protein genetics, Wnt-5a Protein metabolism, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
Genome methylation profiles define naïve-like (n-CLL), memory-like (m-CLL), and intermediate (i-CLL) subsets of chronic lymphocytic leukaemia (CLL). The profiles can be easily determined by the analysis of the five-CpG signature. m-CLL, i-CLL, and n-CLL with the good, intermediate, and poor prognoses, respectively, differ by the somatic hypermutation status of the immunoglobulin heavy chain variable gene (IGHV), a widely used prognostic predictor in CLL. We have previously shown that the expression of WNT5A , encoding a ROR1 ligand, distinguishes patients with the worse outcome within the prognostically favourable IGHV-mutated subgroup. To analyse the mechanisms controlling WNT5A expression, we investigated the methylation status of 54 CpG sites within the WNT5A promoter and its relation to the WNT5A gene expression. In a cohort of 59 CLL patients balanced for combinations of IGHV and WNT5A statuses, we identified three promoter CpG sites whose methylation level correlated with the WNT5A expression within the IGHV-mutated subgroup. Further, we complemented our data with the methylation status of the five-CpG signature. IGHV-mutated/ WNT5A -negative and IGHV-mutated/ WNT5A -positive cases overlapped with m‑CLL and i‑CLL methylation subgroups, respectively, while most IGHV‑unmutated samples were assigned to n-CLL. Median methylation levels of all the three CpG sites in the WNT5A promoter were lowest in i-CLL. Finally, a detailed analysis of m-CLL and i-CLL showed that undetectable WNT5A expression predicts longer treatment-free survival with higher statistical significance than the classification according to the five-CpG signature. To conclude, a favourable m-CLL subgroup is associated with mutated IGHV and undetectable WNT5A expression due to its promoter methylation.
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- 2022
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32. Evolution of TP53 abnormalities during CLL disease course is associated with telomere length changes.
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Olbertova H, Plevova K, Pavlova S, Malcikova J, Kotaskova J, Stranska K, Spunarova M, Trbusek M, Navrkalova V, Dvorackova B, Tom N, Pal K, Jarosova M, Brychtova Y, Panovska A, Doubek M, and Pospisilova S
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- Female, Humans, Male, Middle Aged, Mutation, Proto-Oncogene Proteins c-bcr metabolism, Signal Transduction, Telomerase genetics, Clonal Evolution genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Telomere ultrastructure, Tumor Suppressor Protein p53 genetics
- Abstract
Background: Telomeres are protective structures at chromosome ends which shorten gradually with increasing age. In chronic lymphocytic leukemia (CLL), short telomeres have been associated with unfavorable disease outcome, but the link between clonal evolution and telomere shortening remains unresolved., Methods: We investigated relative telomere length (RTL) in a well-characterized cohort of 198 CLL patients by qPCR and focused in detail on a subgroup 26 patients who underwent clonal evolution of TP53 mutations (evolTP53). In the evolTP53 subgroup we explored factors influencing clonal evolution and corresponding changes in telomere length through measurements of telomerase expression, lymphocyte doubling time, and BCR signaling activity., Results: At baseline, RTL of the evolTP53 patients was scattered across the entire RTL spectrum observed in our CLL cohort. RTL changed in the follow-up samples of 16/26 (62%) evolTP53 cases, inclining to reach intermediate RTL values, i.e., longer telomeres shortened compared to baseline while shorter ones prolonged. For the first time we show that TP53 clonal shifts are linked to RTL change, including unexpected RTL prolongation. We further investigated parameters associated with RTL changes. Unstable telomeres were significantly more frequent among younger patients (P = 0.032). Shorter telomeres were associated with decreased activity of the B-cell receptor signaling components p-ERK1/2, p-ZAP-70/SYK, and p-NFκB (P = 0.04, P = 0.01, and P = 0.02, respectively)., Conclusions: Our study revealed that changes of telomere length reflect evolution in leukemic subclone proportion, and are associated with specific clinico-biological features of the explored cohort., (© 2022. The Author(s).)
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- 2022
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33. Low-burden TP53 mutations in CLL: clinical impact and clonal evolution within the context of different treatment options.
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Malcikova J, Pavlova S, Kunt Vonkova B, Radova L, Plevova K, Kotaskova J, Pal K, Dvorackova B, Zenatova M, Hynst J, Ondrouskova E, Panovska A, Brychtova Y, Zavacka K, Tichy B, Tom N, Mayer J, Doubek M, and Pospisilova S
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- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Female, Humans, Immunotherapy, Kaplan-Meier Estimate, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Male, Middle Aged, Mutation drug effects, Tumor Cells, Cultured, Clonal Evolution drug effects, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Tumor Suppressor Protein p53 genetics
- Abstract
Patients with chronic lymphocytic leukemia (CLL) bearing TP53 mutations experience chemorefractory disease and are therefore candidates for targeted therapy. However, the significance of low-burden TP53 mutations with <10% variant allele frequency (VAF) remains a matter for debate. Herein, we describe clonal evolution scenarios of low-burden TP53 mutations, the clinical impact of which we analyzed in a "real-world" CLL cohort. TP53 status was assessed by targeted next-generation sequencing (NGS) in 511 patients entering first-line treatment with chemo- and/or immunotherapy and 159 patients in relapse before treatment with targeted agents. Within the pretherapy cohort, 16% of patients carried low-burden TP53 mutations (0.1% to 10% VAF). Although their presence did not significantly shorten event-free survival after first-line therapy, it affected overall survival (OS). In a subgroup with TP53 mutations of 1% to 10% VAF, the impact on OS was observed only in patients with unmutated IGHV who had not received targeted therapy, as patients benefited from switching to targeted agents, regardless of initial TP53 mutational status. Analysis of the clonal evolution of low-burden TP53 mutations showed that the highest expansion rates were associated with fludarabine, cyclophosphamide, and rituximab regimen in both first- and second-line treatments (median VAF increase, 14.8× and 11.8×, respectively) in contrast to treatment with less intense treatment regimens (1.6×) and no treatment (0.8×). In the relapse cohort, 33% of patients carried low-burden TP53 mutations, which did not expand significantly upon targeted treatment (median VAF change, 1×). Sporadic cases of TP53 mutations' clonal shifts were connected with the development of resistance-associated mutations. Altogether, our data support the incorporation of low-burden TP53 variants in clinical decision making., (© 2021 by The American Society of Hematology.)
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- 2021
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34. LYmphoid NeXt-Generation Sequencing (LYNX) Panel: A Comprehensive Capture-Based Sequencing Tool for the Analysis of Prognostic and Predictive Markers in Lymphoid Malignancies.
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Navrkalova V, Plevova K, Hynst J, Pal K, Mareckova A, Reigl T, Jelinkova H, Vrzalova Z, Stranska K, Pavlova S, Panovska A, Janikova A, Doubek M, Kotaskova J, and Pospisilova S
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- Chromosome Aberrations, Computational Biology methods, DNA Copy Number Variations, Genetic Variation, Genomics methods, Humans, INDEL Mutation, Molecular Diagnostic Techniques, Prognosis, Translocation, Genetic, Biomarkers, Tumor, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing methods, Leukemia, Lymphoid diagnosis, Leukemia, Lymphoid genetics, Lymphoma diagnosis, Lymphoma genetics
- Abstract
B-cell neoplasms represent a clinically heterogeneous group of hematologic malignancies with considerably diverse genomic architecture recently endorsed by next-generation sequencing (NGS) studies. Because multiple genetic defects have a potential or confirmed clinical impact, a tendency toward more comprehensive testing of diagnostic, prognostic, and predictive markers is desired. This study introduces the design, validation, and implementation of an integrative, custom-designed, capture-based NGS panel titled LYmphoid NeXt-generation sequencing (LYNX) for the analysis of standard and novel molecular markers in the most common lymphoid neoplasms (chronic lymphocytic leukemia, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma). A single LYNX test provides the following: i) accurate detection of mutations in all coding exons and splice sites of 70 lymphoma-related genes with a sensitivity of 5% variant allele frequency, ii) reliable identification of large genome-wide (≥6 Mb) and recurrent chromosomal aberrations (≥300 kb) in at least 20% of the clonal cell fraction, iii) the assessment of immunoglobulin and T-cell receptor gene rearrangements, and iv) lymphoma-specific translocation detection. Dedicated bioinformatic pipelines were designed to detect all markers mentioned above. The LYNX panel represents a comprehensive, up-to-date tool suitable for routine testing of lymphoid neoplasms with research and clinical applicability. It allows a wide adoption of capture-based targeted NGS in clinical practice and personalized management of patients with lymphoproliferative diseases., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
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- 2021
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35. International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia.
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Condoluci A, Terzi di Bergamo L, Langerbeins P, Hoechstetter MA, Herling CD, De Paoli L, Delgado J, Rabe KG, Gentile M, Doubek M, Mauro FR, Chiodin G, Mattsson M, Bahlo J, Cutrona G, Kotaskova J, Deambrogi C, Smedby KE, Spina V, Bruscaggin A, Wu W, Moia R, Bianchi E, Gerber B, Zucca E, Gillessen S, Ghielmini M, Cavalli F, Stussi G, Hess MA, Baumann TS, Neri A, Ferrarini M, Rosenquist R, Forconi F, Foà R, Pospisilova S, Morabito F, Stilgenbauer S, Döhner H, Parikh SA, Wierda WG, Montserrat E, Gaidano G, Hallek M, and Rossi D
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- Aged, Combined Modality Therapy, Disease Progression, Female, Follow-Up Studies, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Male, Prognosis, Retrospective Studies, Survival Rate, Biomarkers, Tumor genetics, Clinical Trials as Topic statistics & numerical data, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Mutation, Nomograms
- Abstract
Most patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL [IPS-E]). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials., (© 2020 by The American Society of Hematology.)
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- 2020
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36. Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome.
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Bereshchenko O, Lo Re O, Nikulenkov F, Flamini S, Kotaskova J, Mazza T, Le Pannérer MM, Buschbeck M, Giallongo C, Palumbo G, Li Volti G, Pazienza V, Cervinek L, Riccardi C, Krejci L, Pospisilova S, Stewart AF, and Vinciguerra M
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- Animals, Cell Differentiation, Chromosome Deletion, Chromosomes, Human, Pair 5 genetics, Disease Models, Animal, Epigenesis, Genetic, Haploinsufficiency, Hematopoietic Stem Cells chemistry, Humans, Mice, Mutation, RNA Splice Sites, Sequence Analysis, RNA, Anemia, Macrocytic genetics, Down-Regulation, Hematopoietic Stem Cells cytology, Histones genetics, Myelodysplastic Syndromes genetics
- Abstract
Background: Epigenetic regulation is important in hematopoiesis, but the involvement of histone variants is poorly understood. Myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic stem cell (HSC) disorders characterized by ineffective hematopoiesis. MacroH2A1.1 is a histone H2A variant that negatively correlates with the self-renewal capacity of embryonic, adult, and cancer stem cells. MacroH2A1.1 is a target of the frequent U2AF1 S34F mutation in MDS. The role of macroH2A1.1 in hematopoiesis is unclear., Results: MacroH2A1.1 mRNA levels are significantly decreased in patients with low-risk MDS presenting with chromosomal 5q deletion and myeloid cytopenias and tend to be decreased in MDS patients carrying the U2AF1 S34F mutation. Using an innovative mouse allele lacking the macroH2A1.1 alternatively spliced exon, we investigated whether macroH2A1.1 regulates HSC homeostasis and differentiation. The lack of macroH2A1.1 decreased while macroH2A1.1 haploinsufficiency increased HSC frequency upon irradiation. Moreover, bone marrow transplantation experiments showed that both deficiency and haploinsufficiency of macroH2A1.1 resulted in enhanced HSC differentiation along the myeloid lineage. Finally, RNA-sequencing analysis implicated macroH2A1.1-mediated regulation of ribosomal gene expression in HSC homeostasis., Conclusions: Together, our findings suggest a new epigenetic process contributing to hematopoiesis regulation. By combining clinical data with a discrete mutant mouse model and in vitro studies of human and mouse cells, we identify macroH2A1.1 as a key player in the cellular and molecular features of MDS. These data justify the exploration of macroH2A1.1 and associated proteins as therapeutic targets in hematological malignancies.
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- 2019
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37. CLL cells cumulate genetic aberrations prior to the first therapy even in outwardly inactive disease phase.
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Hernández-Sánchez M, Kotaskova J, Rodríguez AE, Radova L, Tamborero D, Abáigar M, Plevova K, Benito R, Tom N, Quijada-Álamo M, Bikos V, Martín AÁ, Pal K, García de Coca A, Doubek M, López-Bigas N, Hernández-Rivas JM, and Pospisilova S
- Subjects
- Case-Control Studies, Combined Modality Therapy, Follow-Up Studies, Humans, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Longitudinal Studies, Prognosis, Exome Sequencing, Biomarkers, Tumor genetics, Chromosome Aberrations, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Mutation
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- 2019
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38. Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia.
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Baliakas P, Moysiadis T, Hadzidimitriou A, Xochelli A, Jeromin S, Agathangelidis A, Mattsson M, Sutton LA, Minga E, Scarfò L, Rossi D, Davis Z, Villamor N, Parker H, Kotaskova J, Stalika E, Plevova K, Mansouri L, Cortese D, Navarro A, Delgado J, Larrayoz M, Young E, Anagnostopoulos A, Smedby KE, Juliusson G, Sheehy O, Catherwood M, Strefford JC, Stavroyianni N, Belessi C, Pospisilova S, Oscier D, Gaidano G, Campo E, Haferlach C, Ghia P, Rosenquist R, and Stamatopoulos K
- Subjects
- Aged, Aged, 80 and over, Chromosome Aberrations, Female, Humans, Immunogenetics, Kaplan-Meier Estimate, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Male, Mutation, Neoplasm Staging, Prognosis, Time-to-Treatment, Biomarkers, Tumor, Disease Susceptibility, Leukemia, Lymphocytic, Chronic, B-Cell etiology, Leukemia, Lymphocytic, Chronic, B-Cell mortality
- Abstract
Chronic lymphocytic leukemia (CLL) patients with differential somatic hypermutation status of the immunoglobulin heavy variable genes, namely mutated or unmutated, display fundamental clinico-biological differences. Considering this, we assessed prognosis separately within mutated (M-CLL) and unmutated (U-CLL) CLL in 3015 patients, hypothesizing that the relative significance of relevant indicators may differ between these two categories. Within Binet A M-CLL patients, besides TP53 abnormalities, trisomy 12 and stereotyped subset #2 membership were equivalently associated with the shortest time-to-first-treatment and a treatment probability at five and ten years after diagnosis of 40% and 55%, respectively; the remaining cases exhibited 5-year and 10-year treatment probability of 12% and 25%, respectively. Within Binet A U-CLL patients, besides TP53 abnormalities, del(11q) and/or SF3B1 mutations were associated with the shortest time-to-first-treatment (5- and 10-year treatment probability: 78% and 98%, respectively); in the remaining cases, males had a significantly worse prognosis than females. In conclusion, the relative weight of indicators that can accurately risk stratify early-stage CLL patients differs depending on the somatic hypermutation status of the immunoglobulin heavy variable genes of each patient. This finding highlights the fact that compartmentalized approaches based on immunogenetic features are necessary to refine and tailor prognostication in CLL., (Copyright © 2019 Ferrata Storti Foundation.)
- Published
- 2019
- Full Text
- View/download PDF
39. Fragment analysis represents a suitable approach for the detection of hotspot c.7541_7542delCT NOTCH1 mutation in chronic lymphocytic leukemia.
- Author
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Vavrova E, Kantorova B, Vonkova B, Kabathova J, Skuhrova-Francova H, Diviskova E, Letocha O, Kotaskova J, Brychtova Y, Doubek M, Mayer J, and Pospisilova S
- Subjects
- High-Throughput Nucleotide Sequencing, Humans, DNA Mutational Analysis methods, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Mutation, Peptide Fragments analysis, Receptor, Notch1 genetics
- Abstract
The hotspot c.7541_7542delCT NOTCH1 mutation has been proven to have a negative clinical impact in chronic lymphocytic leukemia (CLL). However, an optimal method for its detection has not yet been specified. The aim of our study was to examine the presence of the NOTCH1 mutation in CLL using three commonly used molecular methods. Sanger sequencing, fragment analysis and allele-specific PCR were compared in the detection of the c.7541_7542delCT NOTCH1 mutation in 201 CLL patients. In 7 patients with inconclusive mutational analysis results, the presence of the NOTCH1 mutation was also confirmed using ultra-deep next generation sequencing. The NOTCH1 mutation was detected in 15% (30/201) of examined patients. Only fragment analysis was able to identify all 30 NOTCH1-mutated patients. Sanger sequencing and allele-specific PCR showed a lower detection efficiency, determining 93% (28/30) and 80% (24/30) of the present NOTCH1 mutations, respectively. Considering these three most commonly used methodologies for c.7541_7542delCT NOTCH1 mutation screening in CLL, we defined fragment analysis as the most suitable approach for detecting the hotspot NOTCH1 mutation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
40. Chronic lymphocytic leukemia: A prognostic model comprising only two biomarkers (IGHV mutational status and FISH cytogenetics) separates patients with different outcome and simplifies the CLL-IPI.
- Author
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Delgado J, Doubek M, Baumann T, Kotaskova J, Molica S, Mozas P, Rivas-Delgado A, Morabito F, Pospisilova S, and Montserrat E
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers analysis, Cohort Studies, Genes, Immunoglobulin Heavy Chain, Humans, In Situ Hybridization, Fluorescence, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Middle Aged, Mutation, Prognosis, Risk Assessment, Survival Rate, Young Adult, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis
- Abstract
Rai and Binet staging systems are important to predict the outcome of patients with chronic lymphocytic leukemia (CLL) but do not reflect the biologic diversity of the disease nor predict response to therapy, which ultimately shape patients' outcome. We devised a biomarkers-only CLL prognostic system based on the two most important prognostic parameters in CLL (i.e., IGHV mutational status and fluorescence in situ hybridization [FISH] cytogenetics), separating three different risk groups: (1) low-risk (mutated IGHV + no adverse FISH cytogenetics [del(17p), del(11q)]); (2) intermediate-risk (either unmutated IGHV or adverse FISH cytogenetics) and (3) high-risk (unmutated IGHV + adverse FISH cytogenetics). In 524 unselected subjects with CLL, the 10-year overall survival was 82% (95% CI 76%-88%), 52% (45%-62%), and 27% (17%-42%) for the low-, intermediate-, and high-risk groups, respectively. Patients with low-risk comprised around 50% of the series and had a life expectancy comparable to the general population. The prognostic model was fully validated in two independent cohorts, including 417 patients representative of general CLL population and 337 patients with Binet stage A CLL. The model had a similar discriminatory value as the CLL-IPI. Moreover, it applied to all patients with CLL independently of age, and separated patients with different risk within Rai or Binet clinical stages. The biomarkers-only CLL prognostic system presented here simplifies the CLL-IPI and could be useful in daily practice and to stratify patients in clinical trials., (© 2017 Wiley Periodicals, Inc.)
- Published
- 2017
- Full Text
- View/download PDF
41. Decreased WNT3 expression in chronic lymphocytic leukaemia is a hallmark of disease progression and identifies patients with worse prognosis in the subgroup with mutated IGHV.
- Author
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Poppova L, Janovska P, Plevova K, Radova L, Plesingerova H, Borsky M, Kotaskova J, Kantorova B, Hlozkova M, Figulova J, Brychtova Y, Machalova M, Urik M, Doubek M, Kozubik A, Pospisilova S, Pavlova S, and Bryja V
- Subjects
- Cell Communication, Cell Line, Cohort Studies, Disease Progression, Female, Genes, Immunoglobulin Heavy Chain genetics, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Male, Mutation, Prognosis, Wnt Signaling Pathway, Gene Expression Regulation, Neoplastic, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Wnt3 Protein genetics
- Abstract
The canonical Wnt pathway, dependent on β-catenin-controlled transcription, is the most explored Wnt pathway, known to drive the malignant transformation of multiple cell types. Several reports have suggested that this pathway also participates in chronic lymphocytic leukaemia (CLL) pathogenesis. To get a better insight into the role of the Wnt/β-catenin pathway in CLL we analysed in detail the expression of the most overexpressed Wnt ligand, encoded by the WNT3 gene, in a well-defined cohort of 137 CLL patients. Our analysis demonstrated that (i) untreated patients with more aggressive disease (with a notable exception of patients with 11q deletion) express less WNT3, (ii) WNT3 declines with disease progression in a significant proportion of patients and (iii) low WNT3 was identified as a strong independent marker indicating shorter treatment-free survival in CLL patients with IGHV mutation. Interestingly, CLL-related lymphoid cell lines, but not stromal cells, failed to respond to the ligand-induced activation of the Wnt/β-catenin pathway. This opens the possibility that CLL cells use Wnt-3 to communicate with the cells in the microenvironment. We thus propose that the Wnt/β-catenin pathway plays a more complex role in CLL pathogenesis than previously anticipated., (© 2016 John Wiley & Sons Ltd.)
- Published
- 2016
- Full Text
- View/download PDF
42. Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations.
- Author
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Ljungström V, Cortese D, Young E, Pandzic T, Mansouri L, Plevova K, Ntoufa S, Baliakas P, Clifford R, Sutton LA, Blakemore SJ, Stavroyianni N, Agathangelidis A, Rossi D, Höglund M, Kotaskova J, Juliusson G, Belessi C, Chiorazzi N, Panagiotidis P, Langerak AW, Smedby KE, Oscier D, Gaidano G, Schuh A, Davi F, Pott C, Strefford JC, Trentin L, Pospisilova S, Ghia P, Stamatopoulos K, Sjöblom T, and Rosenquist R
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Blotting, Western, Cell Separation, Cyclophosphamide administration & dosage, DNA Mutational Analysis, Exome, Humans, Immunoprecipitation, Kaplan-Meier Estimate, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Neoplasm Recurrence, Local pathology, Rituximab administration & dosage, Transfection, Tumor Suppressor Protein p53 genetics, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Drug Resistance, Neoplasm genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Mutation, Missense, Neoplasm Recurrence, Local genetics, Ribosomal Proteins genetics
- Abstract
Fludarabine, cyclophosphamide, and rituximab (FCR) is first-line treatment of medically fit chronic lymphocytic leukemia (CLL) patients; however, despite good response rates, many patients eventually relapse. Although recent high-throughput studies have identified novel recurrent genetic lesions in adverse prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, and BIRC3), a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases, selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal before treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid, evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared with wild-type RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology., (© 2016 by The American Society of Hematology.)
- Published
- 2016
- Full Text
- View/download PDF
43. TP53 mutation analysis in chronic lymphocytic leukemia: comparison of different detection methods.
- Author
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Kantorova B, Malcikova J, Smardova J, Pavlova S, Trbusek M, Tom N, Plevova K, Tichy B, Truong S, Diviskova E, Kotaskova J, Oltova A, Patten N, Brychtova Y, Doubek M, Mayer J, and Pospisilova S
- Subjects
- Adult, Aged, Chromatography, High Pressure Liquid, Female, High-Throughput Nucleotide Sequencing, Humans, In Situ Hybridization, Fluorescence, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Genes, p53, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Mutation
- Abstract
TP53 gene defects represent a strong adverse prognostic factor for patient survival and treatment resistance in chronic lymphocytic leukemia (CLL). Although various methods for TP53 mutation analysis have been reported, none of them allow the identification of all occurring sequence variants, and the most suitable methodology is still being discussed. The aim of this study was to determine the limitations of commonly used methods for TP53 mutation examination in CLL and propose an optimal approach for their detection. We examined 182 CLL patients enriched for high-risk cases using denaturing high-performance liquid chromatography (DHPLC), functional analysis of separated alleles in yeast (FASAY), and the AmpliChip p53 Research Test in parallel. The presence of T53 gene mutations was also evaluated using ultra-deep next generation sequencing (NGS) in 69 patients. In total, 79 TP53 mutations in 57 (31 %) patients were found; among them, missense substitutions predominated (68 % of detected mutations). Comparing the efficacy of the methods used, DHPLC and FASAY both combined with direct Sanger sequencing achieved the best results, identifying 95 % and 93 % of TP53-mutated patients. Nevertheless, we showed that in CLL patients carrying low-proportion TP53 mutation, the more sensitive approach, e.g., ultra-deep NGS, might be more appropriate. TP53 gene analysis using DHPLC or FASAY is a suitable approach for mutation detection. Ultra-deep NGS has the potential to overcome shortcomings of methods currently used, allows the detection of minor proportion mutations, and represents thus a promising methodology for near future.
- Published
- 2015
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- View/download PDF
44. High expression of lymphocyte-activation gene 3 (LAG3) in chronic lymphocytic leukemia cells is associated with unmutated immunoglobulin variable heavy chain region (IGHV) gene and reduced treatment-free survival.
- Author
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Kotaskova J, Tichy B, Trbusek M, Francova HS, Kabathova J, Malcikova J, Doubek M, Brychtova Y, Mayer J, and Pospisilova S
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Lipoprotein Lipase genetics, Male, Middle Aged, Mutation, Oligonucleotide Array Sequence Analysis, Reverse Transcriptase Polymerase Chain Reaction, Survival Rate, ZAP-70 Protein-Tyrosine Kinase genetics, Lymphocyte Activation Gene 3 Protein, Antigens, CD genetics, Genes, Immunoglobulin Heavy Chain genetics, Immunoglobulin Variable Region genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
Chronic lymphocytic leukemia (CLL) is characterized by a monoclonal expansion of mature B-lymphocytes. Mutational status of the immunoglobulin variable heavy chain region (IGHV) gene stratifies CLL patients into two prognostic groups. We performed microarray analysis of CLL cells using the Agilent platform to detect the most important gene expression differences regarding IGHV status in CLL cells. We analyzed a cohort of 118 CLL patients with different IGHV mutational status and completely characterized all described prognostic markers using expression microarrays and quantitative real-time RT-PCR (reverse transcription PCR). We detected lymphocyte-activation gene 3 (LAG3) as a novel prognostic marker: LAG3 high expression in CLL cells correlates with unmutated IGHV (P < 0.0001) and reduced treatment-free survival (P = 0.0087). Furthermore, quantitative real-time RT-PCR analysis identified a gene-set (LAG3, LPL, ZAP70) whose overexpression is assigned to unmutated IGHV with 90% specificity (P < 0.0001). Moreover, high expression of tested gene-set and unmutated IGHV equally correlated with reduced treatment-free survival (P = 7.7 * 10(-11) vs. P = 1.8 * 10(-11)). Our results suggest that IGHV status can be precisely assessed using the expression analysis of LAG3, LPL, and ZAP70 genes. Expression data of tested markers provides a similar statistical concordance with treatment-free survival as that of the IGHV status itself. Our findings contribute to the elucidation of CLL pathogenesis and provide novel prognostic markers for possible application in routine diagnostics.
- Published
- 2010
- Full Text
- View/download PDF
45. Inactivation of p53 and amplification of MYCN gene in a terminal lymphoblastic relapse in a chronic lymphocytic leukemia patient.
- Author
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Stano-Kozubik K, Malcikova J, Tichy B, Kotaskova J, Borsky M, Hrabcakova V, Francova H, Valaskova I, Bourkova L, Smardova J, Doubek M, Brychtova Y, Pospisilova S, Mayer J, and Trbusek M
- Subjects
- Gene Amplification, Humans, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Leukemia, Lymphocytic, Chronic, B-Cell prevention & control, Male, Middle Aged, N-Myc Proto-Oncogene Protein, Recurrence, Somatic Hypermutation, Immunoglobulin genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Nuclear Proteins genetics, Oncogene Proteins genetics, Tumor Suppressor Protein p53 genetics
- Abstract
B-cell chronic lymphocytic leukemia (CLL) is an incurable disease with a highly variable clinical course. A proportion of patients eventually progress to a higher stage of malignancy. A recent association has been observed between the presence of aberrant somatic hypermutations in leukemic cells (hypermutations occurring outside of the immunoglobulin locus) and the transformation to a diffuse large B-cell lymphoma or prolymphocytic leukemia. In this study, we report on the rarely observed blastic transformation in a CLL patient who had previously been shown to harbor aberrant somatic hypermutations in the TP53 tumor-suppressor gene (Mol Immunol 2008;45:1525-29). The enzyme responsible, the activation-induced cytidine deaminase, was still active within the transformation, as evidenced by the ongoing class-switch recombination of cytoplasmic immunoglobulins. The transformation was accompanied by a complete p53 inactivation, as well as complex karyotype changes including prominent amplification of MYCN oncogene. Our case-study supports the view that the aberrant somatic hypermutation is associated with transformation of CLL to a more aggressive malignancy.
- Published
- 2009
- Full Text
- View/download PDF
46. [The choice of toys in view of the age and sex of children of the pre-school age].
- Author
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KOTASKOVA J
- Subjects
- Child, Humans, Choice Behavior, Play and Playthings, Schools
- Published
- 1962
47. [PSYCHOLOGICAL METHODS IN CHILD AND ADOLESCENT HYGIENE].
- Author
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KOTASKOVA J
- Subjects
- Adolescent, Child, Czechoslovakia, Humans, Child Welfare, Hygiene, Psychological Techniques, Psychology, Child, State Medicine
- Published
- 1964
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