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2. Unveiling the dynamics and molecular landscape of a rare chronic lymphocytic leukemia subpopulation driving refractoriness: insights from single‐cell RNA sequencing

Author

Kurucova, Terezia, primary, Reblova, Kamila, additional, Janovska, Pavlina, additional, Porc, Jakub Pawel, additional, Navrkalova, Veronika, additional, Pavlova, Sarka, additional, Malcikova, Jitka, additional, Plevova, Karla, additional, Tichy, Boris, additional, Doubek, Michael, additional, Bryja, Vitezslav, additional, Kotaskova, Jana, additional, and Pospisilova, Sarka, additional

Published
2024
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9. Integrative NGS testing reveals clonal dynamics of adverse genomic defects contributing to a natural progression in treatment‐naïve CLL patients.

Author

Navrkalova, Veronika, Plevova, Karla, Radova, Lenka, Porc, Jakub, Pal, Karol, Malcikova, Jitka, Pavlova, Sarka, Doubek, Michael, Panovska, Anna, Kotaskova, Jana, and Pospisilova, Sarka

Subjects
CHRONIC lymphocytic leukemia, CHRONIC leukemia, LYMPHOCYTIC leukemia, GENETIC testing, GENETIC variation
Abstract

Summary: 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. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Mobile retroelements induced by hypomethylating agents are restricted to transpose in myeloid malignancies

Author

Plevova, Karla, primary, Pavlova, Sarka, additional, Krzyzankova, Marcela, additional, Volakhava, Anastasiya, additional, Smirnova, Anastasia, additional, Grigoreva, Tatiana, additional, Jaskova, Zuzana, additional, Synackova, Hana, additional, Wahl, Dennis, additional, Bohunova, Michaela, additional, Cervinek, Libor, additional, Pospisilova, Sarka, additional, and Mamedov, Ilgar, additional

Published
2023
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11. Casein kinase 1 is a therapeutic target in chronic lymphocytic leukemia

Author

Janovska, Pavlina, Verner, Jan, Kohoutek, Jiri, Bryjova, Lenka, Gregorova, Michaela, Dzimkova, Marta, Skabrahova, Hana, Radaszkiewicz, Tomasz, Ovesna, Petra, Vondalova Blanarova, Olga, Nemcova, Tereza, Hoferova, Zuzana, Vasickova, Katerina, Smyckova, Lucie, Egle, Alexander, Pavlova, Sarka, Poppova, Lucie, Plevova, Karla, Pospisilova, Sarka, and Bryja, Vitezslav

Published
2018
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12. ERIC recommendations for TP53mutation analysis in chronic lymphocytic leukemia—2024 update

Author

Malcikova, Jitka, Pavlova, Sarka, Baliakas, Panagiotis, Chatzikonstantinou, Thomas, Tausch, Eugen, Catherwood, Mark, Rossi, Davide, Soussi, Thierry, Tichy, Boris, Kater, Arnon P., Niemann, Carsten U., Davi, Frederic, Gaidano, Gianluca, Stilgenbauer, Stephan, Rosenquist, Richard, Stamatopoulos, Kostas, Ghia, Paolo, and Pospisilova, Sarka

Abstract

In chronic lymphocytic leukemia (CLL), analysis of TP53aberrations (deletion and/or mutation) is a crucial part of treatment decision-making algorithms. Technological and treatment advances have resulted in the need for an update of the last recommendations for TP53analysis in CLL, published by ERIC, the European Research Initiative on CLL, in 2018. Based on the current knowledge of the relevance of low-burden TP53-mutated clones, a specific variant allele frequency (VAF) cut-off for reporting TP53mutations is no longer recommended, but instead, the need for thorough method validation by the reporting laboratory is emphasized. The result of TP53analyses should always be interpreted within the context of available laboratory and clinical information, treatment indication, and therapeutic options. Methodological aspects of introducing next-generation sequencing (NGS) in routine practice are discussed with a focus on reliable detection of low-burden clones. Furthermore, potential interpretation challenges are presented, and a simplified algorithm for the classification of TP53variants in CLL is provided, representing a consensus based on previously published guidelines. Finally, the reporting requirements are highlighted, including a template for clinical reports of TP53aberrations. These recommendations are intended to assist diagnosticians in the correct assessment of TP53mutation status, but also physicians in the appropriate understanding of the lab reports, thus decreasing the risk of misinterpretation and incorrect management of patients in routine practice whilst also leading to improved stratification of patients with CLL in clinical trials.

Published
2024
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14. Supplementary Table 1 from Autocrine Signaling by Wnt-5a Deregulates Chemotaxis of Leukemic Cells and Predicts Clinical Outcome in Chronic Lymphocytic Leukemia

Author

Janovska, Pavlina, primary, Poppova, Lucie, primary, Plevova, Karla, primary, Plesingerova, Hana, primary, Behal, Martin, primary, Kaucka, Marketa, primary, Ovesna, Petra, primary, Hlozkova, Michaela, primary, Borsky, Marek, primary, Stehlikova, Olga, primary, Brychtova, Yvona, primary, Doubek, Michael, primary, Machalova, Michaela, primary, Baskar, Sivasubramanian, primary, Kozubik, Alois, primary, Pospisilova, Sarka, primary, Pavlova, Sarka, primary, and Bryja, Vitezslav, primary

Published
2023
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15. Distinct p53 phosphorylation patterns in chronic lymphocytic leukemia patients are reflected in the activation of circumjacent pathways upon DNA damage

Author

Mancikova, Veronika, primary, Pesova, Michaela, additional, Pavlova, Sarka, additional, Helma, Robert, additional, Zavacka, Kristyna, additional, Hejret, Vaclav, additional, Taus, Petr, additional, Hynst, Jakub, additional, Plevova, Karla, additional, Malcikova, Jitka, additional, and Pospisilova, Sarka, additional

Published
2022
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17. Additional file 1 of Evolution of TP53 abnormalities during CLL disease course is associated with telomere length changes

Author

Olbertova, Helena, Plevova, Karla, Pavlova, Sarka, Malcikova, Jitka, Kotaskova, Jana, Stranska, Kamila, Spunarova, Michaela, Trbusek, Martin, Navrkalova, Veronika, Dvorackova, Barbara, Tom, Nikola, Pal, Karol, Jarosova, Marie, Brychtova, Yvona, Panovska, Anna, Doubek, Michael, and Pospisilova, Sarka

Abstract

Additional file 1: Supplementary Table 1. Antibodies used for BCR signaling activity assessment. Supplementary Table 2. Results of relative telomere length (RTL) quantification in the basic CLL cohort (n = 198). Supplementary Table 3. TP53 mutation evolution cohort ��� overview of clinico-biological features and results in baseline and follow-up samples, PART A Abbreviations: ALZ ��� alemtuzumab; BR - bendamustine and rituximab; CLB ��� chlorambucil; CR - cyclophosphamide and rituximab; del - deletion; F ��� female; FCR - fludarabine, cyclophosphamide, and rituximab; FISH - fluorescence in situ hybridization; hyper CVAD - hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone; IGHV ��� immunoglobulin heavy chain variable region; M ��� male; M ��� mutated; mo ��� months; U ��� unmutated; yrs ��� years. Supplementary Table 3. TP53 mutation evolution cohort ��� overview of clinico-biological features and results in baseline and follow-up samples, PART B Abbreviations: LTD ��� lymphocyte doubling time; mo ��� months; mut ��� mutated; p ��� phosphorylated; RTL ��� relative telomere length; VAF ��� variant allele frequency; wt ��� wildtype. Supplementary Figure 1. RTL of the entire CLL cohort was compared to the telomere length of a control DNA sample pooled from healthy individuals, arbitrarily set to RTL = 1 (green line). Median RTL of CLL cases (black line) was 0.81, range 0.46 ��� 1.25. Supplementary Figure 2. A) Rai (n = 130) and B) Binet (n = 133) stages at diagnosis in untreated CLL samples and their associations with RTL. The significant associations were P 0 vs III-IV = 0.0018; P I-II vs III-IV = 0.0108; P A vs C = 0.0043. Supplementary Figure 3. Overall survival (OS) of A) the entire CLL cohort (n = 198) divided by RTL above (���RTL long���) and below (���RTL short���) median RTL value (median RTL = 0.84; OS long RTL = 119; OS short RTL = 91; OS P = 0.0004); and B) of CLL patients with mutated TP53 status (n = 40) divided by RTL above (���RTL long���) and below (���RTL short���) median RTL value in this subgroup (median RTL = 0.78; OS long RTL = 86; OS short RTL = 55; OS P = 0.046). Supplementary Figure 4. hTERT expression in A) the baseline samples (P shortening vs. stable = 0.66; P stable vs. prolonging = 0.08; P shortening vs. prolonging = 0.45) and in B) the follow-up samples (P shortening vs. stable = 0.77; P stable vs. prolonging = 0.52; P shortening vs. prolonging = 0.82), (RTL shortening n = 10; stable n = 10; prolonging n = 6). C) Comparison of hTERT values in serial samples. hTERT expression did not associate with RTL prolongation. Supplementary Figure 5. Lymphocyte doubling time did not correlate with a change of RTL time during the disease course (Pearson r = -0.175; P = 0.45). Supplementary Figure 6. p-ZAP70/SYK significantly correlated with p-ERK1/2 in A) baseline samples (Pearson R = 0.82; P = 0.002) and B) follow-up samples (Pearson R = 0.92; P < 0.001).

Published
2022
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18. Memory B-cell like chronic lymphocytic leukaemia is associated with specific methylation profile of WNT5A promoter and undetectable expression of WNT5A gene

Author

Poppova, Lucie, Pavlova, Sarka, Gonzalez, Beatriz, Kotaskova, Jana, Plevova, Karla, Dumbovic, Gabrijela, Janovska, Pavlina, Bystry, Vojtech, Panovska, Anna, Bezdekova, Lucie, Maslejova, Stanislava, Brychtova, Yvona, Doubek, Michael, Krzyzankova, Marcela, Borsky, Marek, Mayer, Jiri, Bryja, Vitezslav, Alonso, Sergio, and Pospisilova, Sarka

Subjects
immune system diseases, hemic and lymphatic diseases, embryonic structures, sense organs, neoplasms
Abstract

Genome methylation profiles define na��ve-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.

Published
2022
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19. Distinct p53 phosphorylation patterns in chronic lymphocytic leukemia patients are reflected in the activation of circumjacent pathways upon DNA damage.

Author

Mancikova, Veronika, Pesova, Michaela, Pavlova, Sarka, Helma, Robert, Zavacka, Kristyna, Hejret, Vaclav, Taus, Petr, Hynst, Jakub, Plevova, Karla, Malcikova, Jitka, and Pospisilova, Sarka

Abstract

TP53 gene abnormalities represent the most important biomarker in chronic lymphocytic leukemia (CLL). Altered protein modifications could also influence p53 function, even in the wild‐type protein. We assessed the impact of p53 protein phosphorylations on p53 functions as an alternative inactivation mechanism. We studied p53 phospho‐profiles induced by DNA‐damaging agents (fludarabine, doxorubicin) in 71 TP53‐intact primary CLL samples. Doxorubicin induced two distinct phospho‐profiles: profile I (heavily phosphorylated) and profile II (hypophosphorylated). Profile II samples were less capable of activating p53 target genes upon doxorubicin exposure, resembling TP53‐mutant samples at the transcriptomic level, whereas standard p53 signaling was triggered in profile I. ATM locus defects were more common in profile II. The samples also differed in the basal activity of the hypoxia pathway: the highest level was detected in TP53‐mutant samples, followed by profile II and profile I. Our study suggests that wild‐type TP53 CLL cells with less phosphorylated p53 show TP53‐mutant‐like behavior after DNA damage. p53 hypophosphorylation and the related lower ability to respond to DNA damage are linked to ATM locus defects and the higher basal activity of the hypoxia pathway. [ABSTRACT FROM AUTHOR]

Published
2023
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21. Memory B-cell like chronic lymphocytic leukaemia is associated with specific methylation profile of WNT5A promoter and undetectable expression of WNT5A gene

Author

Poppova, Lucie, primary, Pavlova, Sarka, additional, Gonzalez, Beatriz, additional, Kotaskova, Jana, additional, Plevova, Karla, additional, Dumbovic, Gabrijela, additional, Janovska, Pavlina, additional, Bystry, Vojtech, additional, Panovska, Anna, additional, Bezdekova, Lucie, additional, Maslejova, Stanislava, additional, Brychtova, Yvona, additional, Doubek, Michael, additional, Krzyzankova, Marcela, additional, Borsky, Marek, additional, Mayer, Jiri, additional, Bryja, Vitezslav, additional, Alonso, Sergio, additional, and Pospisilova, Sarka, additional

Published
2022
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22. The Absence of Retroelement Activity Is Characteristic for Childhood Acute Leukemias and Adult Acute Lymphoblastic Leukemia

Author

Urazbakhtin, Shamil, primary, Smirnova, Anastasia, additional, Volakhava, Anastasiya, additional, Zerkalenkova, Elena, additional, Salyutina, Maria, additional, Doubek, Michael, additional, Jelinkova, Hana, additional, Khudainazarova, Nelly, additional, Volchkov, Egor, additional, Belyaeva, Laima, additional, Komech, Ekaterina, additional, Pavlova, Sarka, additional, Lebedev, Yuri, additional, Plevova, Karla, additional, Olshanskaya, Yulia, additional, Komkov, Alexander, additional, and Mamedov, Ilgar, additional

Published
2022
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23. Low-burden TP53 mutations in CLL: clinical impact and clonal evolution within the context of different treatment options

Author

Malcikova, Jitka, primary, Pavlova, Sarka, additional, Kunt Vonkova, Barbara, additional, Radova, Lenka, additional, Plevova, Karla, additional, Kotaskova, Jana, additional, Pal, Karol, additional, Dvorackova, Barbara, additional, Zenatova, Marcela, additional, Hynst, Jakub, additional, Ondrouskova, Eva, additional, Panovska, Anna, additional, Brychtova, Yvona, additional, Zavacka, Kristyna, additional, Tichy, Boris, additional, Tom, Nikola, additional, Mayer, Jiri, additional, Doubek, Michael, additional, and Pospisilova, Sarka, additional

Published
2021
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25. Memory B-cell like chronic lymphocytic leukaemia is associated with specific methylation profile of WNT5Apromoter and undetectable expression of WNT5Agene

Author

Poppova, Lucie, Pavlova, Sarka, Gonzalez, Beatriz, Kotaskova, Jana, Plevova, Karla, Dumbovic, Gabrijela, Janovska, Pavlina, Bystry, Vojtech, Panovska, Anna, Bezdekova, Lucie, Maslejova, Stanislava, Brychtova, Yvona, Doubek, Michael, Krzyzankova, Marcela, Borsky, Marek, Mayer, Jiri, Bryja, Vitezslav, Alonso, Sergio, and Pospisilova, Sarka

Abstract

ABSTRACTGenome 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 WNT5Aexpression, we investigated the methylation status of 54 CpG sites within the WNT5Apromoter and its relation to the WNT5Agene expression. In a cohort of 59 CLL patients balanced for combinations of IGHV and WNT5Astatuses, we identified three promoter CpG sites whose methylation level correlated with the WNT5Aexpression 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 WNT5Apromoter were lowest in i-CLL. Finally, a detailed analysis of m-CLL and i-CLL showed that undetectable WNT5Aexpression 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 WNT5Aexpression due to its promoter methylation.

Published
2022
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26. Identification and functional characterization of new missense SNPs in the coding region of the TP53 gene

Author

Doffe, Flora, primary, Carbonnier, Vincent, additional, Tissier, Manon, additional, Leroy, Bernard, additional, Martins, Isabelle, additional, Mattsson, Johanna S. M., additional, Micke, Patrick, additional, Pavlova, Sarka, additional, Pospisilova, Sarka, additional, Smardova, Jana, additional, Joerger, Andreas C., additional, Wiman, Klas G., additional, Kroemer, Guido, additional, and Soussi, Thierry, additional

Published
2020
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27. Low-burden TP53mutations in CLL: clinical impact and clonal evolution within the context of different treatment options

Author

Malcikova, Jitka, Pavlova, Sarka, Barbara, Kunt Vonkova, Radova, Lenka, Plevova, Karla, Kotaskova, Jana, Pal, Karol, Dvorackova, Barbara, Zenatova, Marcela, Hynst, Jakub, Ondrouskova, Eva, Panovska, Anna, Brychtova, Yvona, Zavacka, Kristyna, Tichy, Boris, Tom, Nikola, Mayer, Jiri, Doubek, Michael, and Pospisilova, Sarka

Abstract

Patients with chronic lymphocytic leukemia (CLL) bearing TP53mutations experience chemorefractory disease and are therefore candidates for targeted therapy. However, the significance of low-burden TP53mutations with <10% variant allele frequency (VAF) remains a matter for debate. Herein, we describe clonal evolution scenarios of low-burden TP53mutations, the clinical impact of which we analyzed in a “real-world” CLL cohort. TP53status 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 TP53mutations (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 TP53mutations 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 TP53mutational status. Analysis of the clonal evolution of low-burden TP53mutations 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 TP53mutations, which did not expand significantly upon targeted treatment (median VAF change, 1×). Sporadic cases of TP53mutations' clonal shifts were connected with the development of resistance-associated mutations. Altogether, our data support the incorporation of low-burden TP53variants in clinical decision making.

Published
2021
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28. 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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29. Laboratories Can Reliably Detect Clinically Relevant Variants in the TP53Gene below 10 % Allelic Frequency: A Multicenter Study of ERIC, the European Research Initiative on CLL

Author

Pavlova, Sarka, Malcikova, Jitka, Radova, Lenka, Bonfiglio, Silvia, Cowland, Jack B., Brieghel, Christian, Andersen, Mette Klarskov, Karypidou, Maria, Biderman, Bella V, Doubek, Michael, Lazarian, Gregory, Rapado, Inmaculada, Vynck, Matthijs, Porret, Naomi, Andres, Martin, Rosenberg, Dina, Sahar, Dvora, Martinez-Laperche, Carolina, Borde, Ismael Buño, Hindley, Andrew, Sánchez, Julio Bravo, García-Marco, José, Serrano, Alicia, Ferrer Lores, Blanca, Fernández-Rodriguez, Concepción, Bellosillo, Beatriz, Stilgenbauer, Stephan, Tausch, Eugen, Nikdin, Hero, Quinn, Fiona, Atkinson, Emer, Van De Corput, Lisette, Yildiz, Cafer, Bilbao, Cristina, Florido, Yanira, Thiede, Christian, Schuster, Caroline, Stoj, Anastazja, Czekalska, Sylwia, Chatzidimitriou, Anastasia, Laidou, Stamatia, Bidet, Audrey, Dussiau, Charles, Nollet, Friedel, Piras, Giovanna, Borosova, Tereza, Kurucova, Terezia, Monne, Maria, Smirnova, Svetlana, Nikitin, Evgeny, Sloma, Ivan, Delfau, Marie-Helene, Largeaud, Laetitia, Ysebaert, Loic, Valk, Peter J. M., Christian, Amy, Walewska, Renata, Sebastião, Marta, da Silva, Maria Gomes, Galieni, Piero, Angelini, Mario, Rossi, Davide, Spina, Valeria, Matos, Sónia, Martins, Vânia, Donaldson, David, Stoklosa, Tomasz, Pepek, Monika, Baliakas, Panagiotis, Andreu, Rafa, Luna, Irene, Kahre, Tiina, Murumets, Ülle, Laird, Sophie, Ward, Daniel, Alcoceba, Miguel, Balanzategui, Ana, Scarfo, Lydia, Gandini, Francesca, Zapparoli, Ettore, Blanco, Adoracion, Costa, Pau Abrisqueta, Rodriguez, Ana E., Benito Sanchez, Maria Rocio, Davi, Frédéric, Bravetti, Clothilde, Gameiro, Paula, Martinez-Lopez, Joaquin, Tazon, Barbara, Baran-Marszak, Fanny, Davies, Zadie, Caterwood, Mark, Sudarikov, Andrey B, Rosenquist, Richard, Niemann, Carsten Utoft, Stamatopoulos, Kostas, Ghia, Paolo, and Pospisilova, Sarka

Abstract

The presence of mutations in the TP53gene is a powerful prognostic and predictive marker in chronic lymphocytic leukemia (CLL). Widespread use of NGS has enabled the detection of variants ≤10 % variant allelic frequency (low-VAF variants); however, the overall reliability and reproducibility of NGS techniques to identify such variants have been questioned repeatedly. Individual studies using sensitive, custom NGS-based assays have mostly demonstrated the shortened overall survival (OS) and event-free survival in patients with low-VAF TP53variants treated with chemoimmunotherapy (CIT) regimens with median survival ranging between that of TP53 variants >10 % VAF (high-VAF) and wild-type TP53(wt- TP53).

Published
2023
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30. Second Line Treatment with Bruton Tyrosine Kinase Inhibitor (BTKi) or Bcl-2 Inhibitor (Bcl-2i) in Patients with Chronic Lymphocytic Leukemia (CLL): Primary Analysis of the Czech Study Group for CLL (CSCLL)

Author

Mihalyova, Jana, Panovska, Anna, Simkovic, Martin, Turcsanyi, Peter, Spacek, Martin, Brejcha, Martin, Lysak, Daniel, Mocikova, Heidi, Pavlova, Sarka, Chrapava, Marika, Zuchnicka, Jana, Brychtova, Yvona, Vodarek, Pavel, Urbanova, Renata, Likarova, Tereza, Malcikova, Jitka, Jurkova, Tereza, Lancova, Klara, Bezdekova, Lucie, Papajik, Tomas, Baranova, Jana, Arpas, Tomas, Pospisilova, Sarka, Smolej, Lukas, and Doubek, Michael

Abstract

Introduction:

Published
2023
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31. DecreasedWNT3expression in chronic lymphocytic leukaemia is a hallmark of disease progression and identifies patients with worse prognosis in the subgroup with mutatedIGHV

Author

Poppova, Lucie, primary, Janovska, Pavlina, additional, Plevova, Karla, additional, Radova, Lenka, additional, Plesingerova, Hana, additional, Borsky, Marek, additional, Kotaskova, Jana, additional, Kantorova, Barbara, additional, Hlozkova, Michaela, additional, Figulova, Jana, additional, Brychtova, Yvona, additional, Machalova, Michaela, additional, Urik, Milan, additional, Doubek, Michael, additional, Kozubik, Alois, additional, Pospisilova, Sarka, additional, Pavlova, Sarka, additional, and Bryja, Vitezslav, additional

Published
2016
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32. Autocrine Signaling by Wnt-5a Deregulates Chemotaxis of Leukemic Cells and Predicts Clinical Outcome in Chronic Lymphocytic Leukemia

Author

Janovska, Pavlina, primary, Poppova, Lucie, additional, Plevova, Karla, additional, Plesingerova, Hana, additional, Behal, Martin, additional, Kaucka, Marketa, additional, Ovesna, Petra, additional, Hlozkova, Michaela, additional, Borsky, Marek, additional, Stehlikova, Olga, additional, Brychtova, Yvona, additional, Doubek, Michael, additional, Machalova, Michaela, additional, Baskar, Sivasubramanian, additional, Kozubik, Alois, additional, Pospisilova, Sarka, additional, Pavlova, Sarka, additional, and Bryja, Vitezslav, additional

Published
2016
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35. TP53 mutation analysis in chronic lymphocytic leukemia: comparison of different detection methods

Author

Kantorova, Barbara, primary, Malcikova, Jitka, additional, Smardova, Jana, additional, Pavlova, Sarka, additional, Trbusek, Martin, additional, Tom, Nikola, additional, Plevova, Karla, additional, Tichy, Boris, additional, Truong, Sim, additional, Diviskova, Eva, additional, Kotaskova, Jana, additional, Oltova, Alexandra, additional, Patten, Nancy, additional, Brychtova, Yvona, additional, Doubek, Michael, additional, Mayer, Jiri, additional, and Pospisilova, Sarka, additional

Published
2014
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36. Prognostic Impact of NOTCH1 Hotspot Mutation in TP53-Mutated Patients with Chronic Lymphocytic Leukemia

Author

Kantorova, Barbara, primary, Malcikova, Jitka, additional, Navrkalova, Veronika, additional, Smardova, Jana, additional, Brazdilova, Kamila, additional, Plevova, Karla, additional, Diviskova, Eva, additional, Borsky, Marek, additional, Pavlova, Sarka, additional, Tom, Nikola, additional, Pal, Karol, additional, Trbusek, Martin, additional, Oltova, Alexandra, additional, Brychtova, Yvona, additional, Doubek, Michael, additional, Mayer, Jiri, additional, and Pospisilova, Sarka, additional

Published
2014
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37. 4.23 MDM2 Promotor Polymorphism and Disease Characteristics in CLL: Individual Patient Data Meta-Analysis of 2598 CLL Patients

Author

Benner, Axel, Mansouri, Larry, Rossi, Davide, Majid, Aneela, Willander, Kerstin, Parker, Anton, Bond, Gareth, Pavlova, Sarka, Nückel, Holger, Merkel, Olaf, Kaderi, Mohd Arifin, Rosenquist, Richard, Gaidano, Gianluca, Dyer, Martin, Söderkvist, Peter, Linderholm, Mats, Oscier, David, Pospisilova, Sarka, Dührsen, Ulrich, Greil, Richard, Döhner, Hartmut, Stilgenbauer, Stephan, and Zenz, Thorsten

Published
2011
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38. 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

Poppova, Lucie, Janovska, Pavlina, Plevova, Karla, Radova, Lenka, Plesingerova, Hana, Borsky, Marek, Kotaskova, Jana, Kantorova, Barbara, Hlozkova, Michaela, Figulova, Jana, Brychtova, Yvona, Machalova, Michaela, Urik, Milan, Doubek, Michael, Kozubik, Alois, Pospisilova, Sarka, Pavlova, Sarka, and Bryja, Vitezslav

Subjects
LYMPHOCYTIC leukemia, WNT signal transduction, PROGNOSIS, BIOMARKERS, B cells
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. [ABSTRACT FROM AUTHOR]

Published
2016
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41. Microrna-34a As a Marker for Fludarabine Resistance and Impairment of p53-Pathway in Chronic Lymphocytic Leukemia

Author

Mraz, Marek, primary, Cerna, Katerina, additional, Mayerova, Veronika, additional, Musilova, Katerina, additional, Plevova, Karla, additional, Pavlova, Sarka, additional, Tichy, Boris, additional, Doubek, Michael, additional, Brychtova, Yvona, additional, Malcikova, Jitka, additional, Mayer, Jiri, additional, Trbusek, Martin, additional, and Pospisilova, Sarka, additional

Published
2012
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42. Gene expression profiling of acute graft-vs-host disease after hematopoietic stem cell transplantation

Author

Verner, Jan, primary, Kabathova, Jitka, additional, Tomancova, Alexandra, additional, Pavlova, Sarka, additional, Tichy, Boris, additional, Mraz, Marek, additional, Brychtova, Yvona, additional, Krejci, Marta, additional, Zdrahal, Zbynek, additional, Trbusek, Martin, additional, Volejnikova, Jana, additional, Sedlacek, Petr, additional, Doubek, Michael, additional, Mayer, Jiri, additional, and Pospisilova, Sarka, additional

Published
2012
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43. The Regulation, Targets and Clinical Relevance of Microrna Mir-650 in Chronic Lymphocytic Leukemia (CLL),

Author

Mraz, Marek, primary, Plevova, Karla, additional, Dolezalova, Dasa, additional, Stano-Kozubik, Katerina, additional, Mayerova, Veronika, additional, Cerna, Katerina, additional, Musilova, Katerina, additional, Pavlova, Sarka, additional, Tichy, Boris, additional, Lochmanova, Jana, additional, Doubek, Michael, additional, Brychtova, Yvona, additional, Trbusek, Martin, additional, Hampl, Ales, additional, Mayer, Jiri, additional, and Pospisilova, Sarka, additional

Published
2011
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44. Mutational Analysis of Mir-29 Family Members in Chronic Lymphocytic Leukemia

Author

Lochmanova, Jana, primary, Mraz, Marek, additional, Navrkalova, Veronika, additional, Dvorakova, Barbora, additional, Tichy, Boris, additional, Plevova, Karla, additional, Sebejova, Ludmila, additional, Malcikova, Jitka, additional, Pavlova, Sarka, additional, Benes, Vladimir, additional, Rausch, Tobias, additional, Brychtova, Yvona, additional, Doubek, Michael, additional, Trbusek, Martin, additional, Mayer, Jiri, additional, and Pospisilova, Sarka, additional

Published
2011
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46. Detail Characterization of 22q11 Deletion and Mir-650 Role in CLL Patients.

Author

Mraz, Marek, primary, Malinova, Karla, additional, Pavlova, Sarka, additional, Tichy, Boris, additional, Kozubik, Katerina Stano, additional, Malcikova, Jitka, additional, Borsky, Marek, additional, Verner, Jan, additional, Doubek, Michael, additional, Brychtova, Yvona, additional, Trbusek, Martin, additional, Mayer, Jiri, additional, and Pospisilova, Sarka, additional

Published
2009
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49. A Comprehensive Capture-Based Sequencing Tool for the Analysis of Prognostic and Predictive Markers in Lymphoid Malignant Tumors

Author

Navrkalova, Veronika, Plevova, Karla, Hynst, Jakub, Pal, Karol, Mareckova, Andrea, Reigl, Tomas, Jelinkova, Hana, Vrzalova, Zuzana, Stranska, Kamila, Pavlova, Sarka, Panovska, Anna, Janikova, Andrea, Doubek, Michael, Kotaskova, Jana, and Pospisilova, Sarka

Abstract

B-cell neoplasms represent a clinically heterogeneous group of hematologic malignant tumors 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 LYNX (Lymphoid Next-Generation Sequencing) for the analysis of standard and novel molecular markers in the most common lymphoid malignant tumors (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 neoplasm with research and clinical applicability. It allows a wide adoption of capture-targeted NGS in clinical practice and personalized management of patients with lymphoproliferative diseases.

Published
2021
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