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1. Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY

Author

Mansouri, Larry, Thorvaldsdottir, Birna, Sutton, Lesley-Ann, Karakatsoulis, Georgios, Meggendorfer, Manja, Parker, Helen, Nadeu, Ferran, Brieghel, Christian, Laidou, Stamatia, Moia, Riccardo, Rossi, Davide, Catherwood, Mark, Kotaskova, Jana, Delgado, Julio, Rodríguez-Vicente, Ana E., Benito, Rocío, Rigolin, Gian Matteo, Bonfiglio, Silvia, Scarfo, Lydia, Mattsson, Mattias, Davis, Zadie, Gogia, Ajay, Rani, Lata, Baliakas, Panagiotis, Foroughi-Asl, Hassan, Jylhä, Cecilia, Skaftason, Aron, Rapado, Inmaculada, Miras, Fatima, Martinez-Lopez, Joaquín, de la Serna, Javier, Rivas, Jesús María Hernández, Thornton, Patrick, Larráyoz, María José, Calasanz, María José, Fésüs, Viktória, Mátrai, Zoltán, Bödör, Csaba, Smedby, Karin E., Espinet, Blanca, Puiggros, Anna, Gupta, Ritu, Bullinger, Lars, Bosch, Francesc, Tazón-Vega, Bárbara, Baran-Marszak, Fanny, Oscier, David, Nguyen-Khac, Florence, Zenz, Thorsten, Terol, Maria Jose, Cuneo, Antonio, Hernández-Sánchez, María, Pospisilova, Sarka, Mills, Ken, Gaidano, Gianluca, Niemann, Carsten U., Campo, Elias, Strefford, Jonathan C., Ghia, Paolo, Stamatopoulos, Kostas, and Rosenquist, Richard

Published
2023
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2. Other malignancies in the history of CLL: an international multicenter study conducted by ERIC, the European Research Initiative on CLL, in HARMONY

Author

Chatzikonstantinou, Thomas, Scarfò, Lydia, Karakatsoulis, Georgios, Minga, Eva, Chamou, Dimitra, Iacoboni, Gloria, Kotaskova, Jana, Demosthenous, Christos, Smolej, Lukas, Mulligan, Stephen, Alcoceba, Miguel, Al-Shemari, Salem, Aurran-Schleinitz, Thérèse, Bacchiarri, Francesca, Bellido, Mar, Bijou, Fontanet, Calleja, Anne, Medina, Angeles, Khan, Mehreen Ali, Cassin, Ramona, Chatzileontiadou, Sofia, Collado, Rosa, Christian, Amy, Davis, Zadie, Dimou, Maria, Donaldson, David, Santos, Gimena Dos, Dreta, Barbara, Efstathopoulou, Maria, El-Ashwah, Shaimaa, Enrico, Alicia, Fresa, Alberto, Galimberti, Sara, Galitzia, Andrea, García-Serra, Rocío, Gimeno, Eva, González-Gascón-y-Marín, Isabel, Gozzetti, Alessandro, Guarente, Valerio, Guieze, Romain, Gogia, Ajay, Gupta, Ritu, Harrop, Sean, Hatzimichael, Eleftheria, Herishanu, Yair, Hernández-Rivas, José-Ángel, Inchiappa, Luca, Jaksic, Ozren, Janssen, Susanne, Kalicińska, Elżbieta, Laribi, Kamel, Karakus, Volkan, Kater, Arnon P., Kho, Bonnie, Kislova, Maria, Konstantinou, Eliana, Koren-Michowitz, Maya, Kotsianidis, Ioannis, Kreitman, Robert J., Labrador, Jorge, Lad, Deepesh, Levin, Mark-David, Levy, Ilana, Longval, Thomas, Lopez-Garcia, Alberto, Marquet, Juan, Martin-Rodríguez, Lucia, Maynadié, Marc, Maslejova, Stanislava, Mayor-Bastida, Carlota, Mihaljevic, Biljana, Milosevic, Ivana, Miras, Fatima, Moia, Riccardo, Morawska, Marta, Murru, Roberta, Nath, Uttam Kumar, Navarro-Bailón, Almudena, Oliveira, Ana C., Olivieri, Jacopo, Oscier, David, Panovska-Stavridis, Irina, Papaioannou, Maria, Papajík, Tomas, Kubova, Zuzana, Phumphukhieo, Punyarat, Pierie, Cheyenne, Puiggros, Anna, Rani, Lata, Reda, Gianluigi, Rigolin, Gian Matteo, Ruchlemer, Rosa, Daniel de Deus Santos, Marcos, Schipani, Mattia, Schiwitza, Annett, Shen, Yandong, Simkovic, Martin, Smirnova, Svetlana, Abdelrahman Soliman, Dina Sameh, Spacek, Martin, Tadmor, Tamar, Tomic, Kristina, Tse, Eric, Vassilakopoulos, Theodoros, Visentin, Andrea, Vitale, Candida, von Tresckow, Julia, Vrachiolias, George, Vukovic, Vojin, Walewska, Renata, Wasik-Szczepanek, Ewa, Xu, Zhenshu, Yagci, Munci, Yañez, Lucrecia, Yassin, Mohamed, Zuchnicka, Jana, Angelopoulou, Maria, Antic, Darko, Biderman, Bella, Catherwood, Mark, Claus, Rainer, Coscia, Marta, Cuneo, Antonio, Demirkan, Fatih, Espinet, Blanca, Gaidano, Gianluca, Kalashnikova, Olga B., Laurenti, Luca, Nikitin, Eugene, Pangalis, Gerassimos A., Panagiotidis, Panagiotis, Popov, Viola Maria, Pospisilova, Sarka, Sportoletti, Paolo, Stavroyianni, Niki, Tam, Constantine, Trentin, Livio, Chatzidimitriou, Anastasia, Bosch, Francesc, Doubek, Michael, Ghia, Paolo, and Stamatopoulos, Kostas

Published
2023
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3. 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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5. 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

Author

Mansouri, Larry, Thorvaldsdottir, Birna, Sutton, Lesley-Ann, Karakatsoulis, Georgios, Meggendorfer, Manja, Parker, Helen, Nadeu, Ferran, Brieghel, Christian, Laidou, Stamatia, Moia, Riccardo, Rossi, Davide, Catherwood, Mark, Kotaskova, Jana, Delgado, Julio, Rodríguez-Vicente, Ana E., Benito, Rocío, Rigolin, Gian Matteo, Bonfiglio, Silvia, Scarfo, Lydia, Mattsson, Mattias, Davis, Zadie, Gogia, Ajay, Rani, Lata, Baliakas, Panagiotis, Foroughi-Asl, Hassan, Jylhä, Cecilia, Skaftason, Aron, Rapado, Inmaculada, Miras, Fatima, Martinez-Lopez, Joaquín, de la Serna, Javier, Rivas, Jesús María Hernández, Thornton, Patrick, Larráyoz, María José, Calasanz, María José, Fésüs, Viktória, Mátrai, Zoltán, Bödör, Csaba, Smedby, Karin E., Espinet, Blanca, Puiggros, Anna, Gupta, Ritu, Bullinger, Lars, Bosch, Francesc, Tazón-Vega, Bárbara, Baran-Marszak, Fanny, Oscier, David, Nguyen-Khac, Florence, Zenz, Thorsten, Terol, Maria Jose, Cuneo, Antonio, Hernández-Sánchez, María, Pospisilova, Sarka, Mills, Ken, Gaidano, Gianluca, Niemann, Carsten U., Campo, Elias, Strefford, Jonathan C., Ghia, Paolo, Stamatopoulos, Kostas, and Rosenquist, Richard

Published
2023
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6. 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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7. P1517: HUMORAL AND CELLULAR IMMUNE RESPONSES TO SARS-COV-2 NATURAL INFECTION OR VACCINATION IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): A STUDY BY ERIC, THE EUROPEAN RESEARCH INITIATIVE ON CLL

Author

Campanella, Alessandro, primary, Capasso, Antonella, additional, Taccetti, Caterina, additional, Heltai, Silvia, additional, Albi, Elisa, additional, Herishanu, Yair, additional, Haggenburg, Sabine, additional, Chatzikonstantinou, Thomas, additional, Doubek, Michael, additional, Kättström, Magdalena, additional, Giannopoulos, Krzysztof, additional, Simkovic, Martin, additional, Moreno, Carol, additional, Massaia, Massimo, additional, Bumbea, Horia, additional, Shimmari, Salem Al, additional, Ranghetti, Pamela, additional, Perotta, Eleonora, additional, Martini, Francesca, additional, Sant’antonio, Emanuela, additional, Colia, Maria, additional, Combi, Catalina, additional, Levi, Shai, additional, Kater, Arnon, additional, Hazenberg, Mette, additional, Nijhof, Inger, additional, Hofsink, Quincy, additional, Demosthenous, Christos, additional, Kotaskova, Jana, additional, Zaleska, Joanna, additional, Vrbacky, Filip, additional, Mora, Alba, additional, Bisogno, Davide, additional, Tripoli, Ignazio Ezio, additional, Popov, Viola Maria, additional, Roman, Viviana, additional, Scarano, Eloise, additional, Frenquelli, Michela, additional, Scarfò, Lydia, additional, Stamatopoulos, Kostas, additional, and Ghia, Paolo, additional

Published
2023
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8. S149: OTHER MALIGNANCIES IN THE HISTORY OF CLL: THE FINAL ANALYSIS OF THE INTERNATIONAL MULTICENTER STUDY CONDUCTED BY ERIC, IN HARMONY.

Author

Chatzikonstantinou, Thomas, primary, Scarfò, Lydia, additional, Karakatsoulis, Georgios, additional, Minga, Eva, additional, Chamou, Dimitra, additional, Iacoboni, Gloria, additional, Kotaskova, Jana, additional, Demosthenous, Christos, additional, Alcoceba, Miguel, additional, Al-Shemari, Salem, additional, Aurran-Schleinitz, Thérèse, additional, Bacchiarri, Francesca, additional, Bellido, Mar, additional, Bijou, Fontanet, additional, Calleja, Anne, additional, Medina, Angeles, additional, Khan, Mehreen Ali, additional, Cassin, Ramona, additional, Chatzileontiadou, Sofia, additional, Collado, Rosa, additional, Davis, Zadie, additional, Dimou, Maria, additional, Donaldson, David, additional, Santos, Gimena Dos, additional, Dreta, Barbara, additional, Efstathopoulou, Maria, additional, El-Ashwah, Shaimaa, additional, Enrico, Alicia, additional, Fresa, Alberto, additional, Galimberti, Sara, additional, Galitzia, Andrea, additional, García-Serra, Rocío, additional, Gimeno, Eva, additional, González-Gascón-Y-Marín, Isabel, additional, Gozzetti, Alessandro, additional, Guarente, Valerio, additional, Guieze, Romain, additional, Gogia, Ajay, additional, Gupta, Ritu, additional, Harrop, Sean, additional, Hatzimichael, Eleftheria, additional, Herishanu, Yair, additional, Hernández-Rivas, José-Ángel, additional, Inchiappa, Luca, additional, Jaksic, Ozren, additional, Janssen, Susanne, additional, Kalicińska, Elżbieta, additional, Kamel, Laribi, additional, Karakus, Volkan, additional, Kater, Arnon P, additional, Kho, Bonnie, additional, Kislova, Maria, additional, Konstantinou, Εliana, additional, Koren-Michowitz, Maya, additional, Kotsianidis, Ioannis, additional, Kreitman, Robert J, additional, Labrador, Jorge, additional, Lad, Deepesh, additional, Levin, Mark-David, additional, Levy, Ilana, additional, Longval, Thomas, additional, Lopez-Garcia, Alberto, additional, Marquet, Juan, additional, Maynadié, Marc, additional, Maslejova, Stanislava, additional, Mayor-Bastida, Carlota, additional, Mihaljevic, Biljana, additional, Milosevic, Ivana, additional, Miras, Fatima, additional, Moia, Riccardo, additional, Morawska, Marta, additional, Murru, Roberta, additional, Nath, Uttam Kumar, additional, Navarro-Bailón, Almudena, additional, Oliveira, Ana C., additional, Olivieri, Jacopo, additional, Oscier, David, additional, Panovska-Stavridis, Irina, additional, Papaioannou, Maria, additional, Papajík, Tomas, additional, Phumphukhieo, Punyarat, additional, Pierie, Cheyenne, additional, Puiggros, Anna, additional, Rani, Lata, additional, Reda, Gianluigi, additional, Rigolin, Gian Matteo, additional, Ronson, Aharon, additional, Ruchlemer, Rosa, additional, de Deus Santos, Marcos Daniel, additional, Schipani, Mattia, additional, Schiwitza, Annett, additional, Shen, Yandong, additional, Simkovic, Martin, additional, Smirnova, Svetlana, additional, Sameh Abdelrahman Soliman, Dina, additional, Spacek, Martin, additional, Tadmor, Tamar, additional, Tomic, Kristina, additional, Tse, Eric, additional, Vassilakopoulos, Theodoros, additional, Visentin, Andrea, additional, Vitale, Candida, additional, Tresckow, Julia von, additional, Vrachiolias, George, additional, Vukovic, Vojin, additional, Walewska, Renata, additional, Wasik-Szczepanek, Ewa, additional, Xu, Zhenshu, additional, Yagci, Munci, additional, Yañez, Lucrecia, additional, Yassin, Mohamed, additional, Zuchnicka, Jana, additional, Angelopoulou, Maria, additional, Antic, Darko, additional, Biderman, Bella, additional, Catherwood, Mark, additional, Claus, Rainer, additional, Coscia, Marta, additional, Cuneo, Antonio, additional, Demirkan, Fatih, additional, Espinet, Blanca, additional, Gaidano, Gianluca, additional, Kalashnikova, Olga, additional, Laurenti, Luca, additional, Nikitin, Eugene, additional, Pangalis, Gerassimos A., additional, Panagiotidis, Panagiotis, additional, Mulligan, Stephen, additional, Popov, Viola Maria, additional, Pospisilova, Sarka, additional, Smolej, Lukas, additional, Sportoletti, Paolo, additional, Stavroyianni, Niki, additional, Tam, Constantine, additional, Trentin, Livio, additional, Chatzidimitriou, Anastasia, additional, Bosch, Francesc, additional, Doubek, Michael, additional, Ghia, Paolo, additional, and Stamatopoulos, Kostas, additional

Published
2023
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9. CLL cells cumulate genetic aberrations prior to the first therapy even in outwardly inactive disease phase

Author

Hernández-Sánchez, María, Kotaskova, Jana, Rodríguez, Ana E, Radova, Lenka, Tamborero, David, Abáigar, María, Plevova, Karla, Benito, Rocío, Tom, Nikola, Quijada-Álamo, Miguel, Bikos, Vasileos, Martín, Ana África, Pal, Karol, García de Coca, Alfonso, Doubek, Michael, López-Bigas, Nuria, Hernández-Rivas, Jesús-María, and Pospisilova, Sarka

Published
2019
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11. Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations

Author

Ljungström, Viktor, Cortese, Diego, Young, Emma, Pandzic, Tatjana, Mansouri, Larry, Plevova, Karla, Ntoufa, Stavroula, Baliakas, Panagiotis, Clifford, Ruth, Sutton, Lesley-Ann, Blakemore, Stuart J., Stavroyianni, Niki, Agathangelidis, Andreas, Rossi, Davide, Höglund, Martin, Kotaskova, Jana, Juliusson, Gunnar, Belessi, Chrysoula, Chiorazzi, Nicholas, Panagiotidis, Panagiotis, Langerak, Anton W., Smedby, Karin E., Oscier, David, Gaidano, Gianluca, Schuh, Anna, Davi, Frederic, Pott, Christiane, Strefford, Jonathan C., Trentin, Livio, Pospisilova, Sarka, Ghia, Paolo, Stamatopoulos, Kostas, Sjöblom, Tobias, and Rosenquist, Richard

Published
2016
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12. Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome

Author

Bereshchenko, Oxana, Lo Re, Oriana, Nikulenkov, Fedor, Flamini, Sara, Kotaskova, Jana, Mazza, Tommaso, Le Pannérer, Marguerite-Marie, Buschbeck, Marcus, Giallongo, Cesarina, Palumbo, Giuseppe, Li Volti, Giovanni, Pazienza, Valerio, Cervinek, Libor, Riccardi, Carlo, Krejci, Lumir, Pospisilova, Sarka, Stewart, A. Francis, and Vinciguerra, Manlio

Published
2019
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13. Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY

Author

Mansouri, Larry, primary, Thorvaldsdottir, Birna, additional, Sutton, Lesley-Ann, additional, Karakatsoulis, Georgios, additional, Meggendorfer, Manja, additional, Parker, Helen, additional, Nadeu, Ferran, additional, Brieghel, Christian, additional, Laidou, Stamatia, additional, Moia, Riccardo, additional, Rossi, Davide, additional, Catherwood, Mark, additional, Kotaskova, Jana, additional, Delgado, Julio, additional, Rodríguez-Vicente, Ana E., additional, Benito, Rocío, additional, Rigolin, Gian Matteo, additional, Bonfiglio, Silvia, additional, Scarfo, Lydia, additional, Mattsson, Mattias, additional, Davis, Zadie, additional, Gogia, Ajay, additional, Rani, Lata, additional, Baliakas, Panagiotis, additional, Foroughi-Asl, Hassan, additional, Jylhä, Cecilia, additional, Skaftason, Aron, additional, Rapado, Inmaculada, additional, Miras, Fatima, additional, Martinez-Lopez, Joaquín, additional, de la Serna, Javier, additional, Rivas, Jesús María Hernández, additional, Thornton, Patrick, additional, Larráyoz, María José, additional, Calasanz, María José, additional, Fésüs, Viktória, additional, Mátrai, Zoltán, additional, Bödör, Csaba, additional, Smedby, Karin E., additional, Espinet, Blanca, additional, Puiggros, Anna, additional, Gupta, Ritu, additional, Bullinger, Lars, additional, Bosch, Francesc, additional, Tazón-Vega, Bárbara, additional, Baran-Marszak, Fanny, additional, Oscier, David, additional, Nguyen-Khac, Florence, additional, Zenz, Thorsten, additional, Terol, Maria Jose, additional, Cuneo, Antonio, additional, Hernández-Sánchez, María, additional, Pospisilova, Sarka, additional, Mills, Ken, additional, Gaidano, Gianluca, additional, Niemann, Carsten U., additional, Campo, Elias, additional, Strefford, Jonathan C., additional, Ghia, Paolo, additional, Stamatopoulos, Kostas, additional, and Rosenquist, Richard, additional

Published
2022
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14. Enabling the Implementation of Next-Generation Sequencing into Clinical Diagnosis: Nemhesys Project

Author

Hernández-Rivas, Jesús María, primary, Serramito-Gómez, Inmaculada, additional, Kallio, Saara, additional, Cantalejo, Amparo, additional, Kotaskova, Jana, additional, Rodriguez, Ana E., additional, Abáigar, María, additional, Benito, Rocio, additional, Dolnik, Anna, additional, Catherwood, Mark, additional, Blayney, Jaine, additional, Tichý, Boris, additional, Chalupová, Ivana, additional, Dubois, Philippe, additional, Lopez, Roberto, additional, Barranquero, Carlos, additional, Lorenzo, María Díaz, additional, Leitzelman, Mylène, additional, Adhikari, Sadiksha, additional, Pospíšilová, Šárka, additional, Bullinger, Lars, additional, Mills, Ken I, additional, and Heckman, Caroline A., additional

Published
2022
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15. 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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16. 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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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, 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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19. 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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20. Different Prognostic Impact of Recurrent Gene Mutations in IGHV-Mutated and IGHV-Unmutated Chronic Lymphocytic Leukemia: A Retrospective, Multi-Center Cohort Study By Eric, the European Research Initiative on CLL, in Harmony

Author

Mansouri, Larry, primary, Thorvaldsdottir, Birna, additional, Sutton, Lesley-Ann, additional, Meggendorfer, Manja, additional, Nadeu, Ferran, additional, Brieghel, Christian, additional, Parker, Helen, additional, Laidou, Stamatia, additional, Moia, Riccardo, additional, Rossi, Davide, additional, Catherwood, Mark, additional, Kotaskova, Jana, additional, Delgado, Julio, additional, Rodríguez-Vicente, Ana E, additional, Benito, Rocio, additional, Rigolin, Gian Matteo, additional, Bonfiglio, Silvia, additional, Scarfo, Lydia, additional, Mattsson, Mattias, additional, Davis, Zadie, additional, Gogia, Ajay, additional, Rani, Lata, additional, Baliakas, Panagiotis, additional, Jylhä, Cecilia, additional, Skaftason, Aron, additional, Rapado, Inmaculada, additional, Miras, Fatima, additional, Martinez-Lopez, Joaquin, additional, de la Serna, Javier, additional, Hernández Rivas, Jesús M, additional, Thornton, Patrick, additional, Larrayoz, Maria Jose, additional, Calasanz, María José, additional, Mátrai, Zoltán, additional, Bodor, Csaba, additional, Smedby, Karin E., additional, Espinet, Blanca, additional, Puiggros, Anna, additional, Gupta, Ritu, additional, Bullinger, Lars, additional, Bosch, Francesc, additional, Tazón, Bárbara, additional, Baran-Marszak, Fanny, additional, Oscier, David, additional, Nguyen-Khac, Florence, additional, Zenz, Thorsten, additional, Terol, María José, additional, Cuneo, Antonio, additional, Hernández-Sánchez, María, additional, Pospisilova, Sarka, additional, Mills, Ken I, additional, Gaidano, Gianluca, additional, Niemann, Carsten Utoft, additional, Campo, Elías, additional, Strefford, Jonathan C, additional, Ghia, Paolo, additional, Stamatopoulos, Kostas, additional, and Rosenquist, Richard, additional

Published
2021
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21. Real-World Evidence on Therapeutic Strategies and Treatment-Sequencing in Patients with Chronic Lymphocytic Leukemia: An International Study of Eric, the European Research Initiative on CLL

Author

Chatzikonstantinou, Thomas, primary, Scarfo, Lydia, additional, Demosthenous, Christos, additional, Kotaskova, Jana, additional, Iacoboni, Gloria, additional, Minga, Evangelia, additional, Chammou, Dimitra, additional, Karakatsoulis, Georgios, additional, Albi, Elisa, additional, Alcoceba, Miguel, additional, El-Ashwah, Shaimaa, additional, Bacchiarri, Francesca, additional, Khan, Mehreen Ali, additional, Aurran, Thérèse, additional, Calleja, Anne, additional, Cassin, Ramona, additional, Chatzileontiadou, Sofia, additional, Christian, Amy, additional, Claus, Rainer, additional, Collado, Rosa, additional, De Deus Santos, Marcos Daniel, additional, Davis, Zadie, additional, Dimou, Maria, additional, Donaldson, David, additional, Dos Santos, Gimena, additional, Dreta, Barbara, additional, Efstathopoulou, Maria, additional, Enrico, Alicia, additional, Fresa, Alberto, additional, Galimberti, Sara, additional, García-Serra, Rocío, additional, González-Gascón Y Marín, Isabel, additional, Gozzetti, Alessandro, additional, Guarente, Valerio, additional, Harrop, Sean, additional, Hatzimichael, Eleftheria, additional, Herishanu, Yair, additional, Inchiappa, Luca, additional, Iskas, Michalis, additional, Jaksic, Ozren, additional, Janssen, Susanne R., additional, Kalicinska, Elzbieta, additional, Karakus, Volkan, additional, Kater, Arnon P., additional, Kho, Bonnie, additional, Konstantinou, Iliana, additional, Longval, Thomas, additional, Koren-Michowitz, Maya, additional, Kotsianidis, Ioannis, additional, Kreitman, Robert J., additional, Nath, Uttam Kumar, additional, Labrador, Jorge, additional, Lad, Deepesh, additional, Laribi, Kamel, additional, Levy, Ilana, additional, Lopez-Garcia, Alberto, additional, Marquet Palomanes, Juan, additional, Maslejova, Stanislava, additional, Mayor-Bastida, Carlota, additional, Merabet, Fatiha, additional, Mihaljevic, Biljana, additional, Milosevic, Ivana, additional, Miras, Fatima, additional, Moia, Riccardo, additional, Morawska, Marta, additional, Navarro-Bailón, Almudena, additional, Oscier, David, additional, Olivieri, Jacopo, additional, Papajík, Tomáš, additional, Papaioannou, Maria, additional, Pierie, Cheyenne, additional, Puiggros, Anna, additional, Reda, Gianluigi, additional, Rigolin, Gian Matteo, additional, Ruchlemer, Rosa, additional, Schiattone, Luana, additional, Sevindik, Omur Gokmen, additional, Shen, Yandong, additional, Šimkovič, Martin, additional, Smirnova, Svetlana, additional, Soliman, Dina Sameh, additional, Špaček, Martin, additional, Schiwitza, Annett, additional, Tadmor, Tamar, additional, Tourjeman, Liat, additional, Tse, Eric, additional, Visentin, Andrea, additional, Tomic, Kristina, additional, Van Gelder, Michel, additional, Vassilakopoulos, Theodoros P., additional, Vitale, Candida, additional, Vrachiolias, George, additional, Vukovic, Vojin, additional, Xu, Zhenshu, additional, Yáñez, Lucrecia, additional, Yagci, Munci, additional, Yassin, Mohamed A, additional, Zuchnicka, Jana, additional, Angelopoulou, Maria K., additional, Antic, Darko, additional, Biderman, Bella V., additional, Catherwood, Mark, additional, Coscia, Marta, additional, Cuneo, Antonio, additional, Demirkan, Fatih, additional, Espinet, Blanca, additional, Gaidano, Gianluca, additional, Guièze, Romain, additional, Kalashnikova, Olga, additional, Laurenti, Luca, additional, Mulligan, Stephen, additional, Murru, Roberta, additional, Nikitin, Eugene A., additional, Panayiotidis, Panayiotis, additional, Pangalis, Gerasimos, additional, Panovska, Irina, additional, Popov, Viola Maria, additional, Pospíšilová, Šárka, additional, Smolej, Lukas, additional, Sportoletti, Paolo, additional, Stavroyianni, Niki, additional, Tam, Constantine S., additional, Trentin, Livio, additional, Trněný, Marek, additional, Bosch Albareda, Francesc, additional, Doubek, Michael, additional, Chatzidimitriou, Anastasia, additional, Ghia, Paolo, additional, and Stamatopoulos, Kostas, additional

Published
2021
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23. 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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24. International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia

Author

Condoluci, Adalgisa, primary, Terzi di Bergamo, Lodovico, primary, Langerbeins, Petra, primary, Hoechstetter, Manuela A., primary, Herling, Carmen D., primary, De Paoli, Lorenzo, primary, Delgado, Julio, primary, Rabe, Kari G., primary, Gentile, Massimo, primary, Doubek, Michael, primary, Mauro, Francesca R., primary, Chiodin, Giorgia, primary, Mattsson, Mattias, primary, Bahlo, Jasmin, primary, Cutrona, Giovanna, primary, Kotaskova, Jana, primary, Deambrogi, Clara, primary, Smedby, Karin E., primary, Spina, Valeria, primary, Bruscaggin, Alessio, primary, Wu, Wei, primary, Moia, Riccardo, primary, Bianchi, Elena, primary, Gerber, Bernhard, primary, Zucca, Emanuele, primary, Gillessen, Silke, primary, Ghielmini, Michele, primary, Cavalli, Franco, primary, Stussi, Georg, primary, Hess, Mark A., primary, Baumann, Tycho S., primary, Neri, Antonino, primary, Ferrarini, Manlio, primary, Rosenquist, Richard, primary, Forconi, Francesco, primary, Foà, Robin, primary, Pospisilova, Sarka, primary, Morabito, Fortunato, primary, Stilgenbauer, Stephan, primary, Döhner, Hartmut, primary, Parikh, Sameer A., primary, Wierda, William G., primary, Montserrat, Emili, primary, Gaidano, Gianluca, primary, Hallek, Michael, primary, and Rossi, Davide, primary

Published
2020
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25. Additional file 3: of Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome

Author

Bereshchenko, Oxana, Re, Oriana Lo, Nikulenkov, Fedor, Flamini, Sara, Kotaskova, Jana, Mazza, Tommaso, Marguerite-Marie Le PannĂŠrer, Buschbeck, Marcus, Giallongo, Cesarina, Palumbo, Giuseppe, Volti, Giovanni Li, Pazienza, Valerio, Cervinek, Libor, Riccardi, Carlo, Krejci, Lumir, Sarka Pospisilova, A. Stewart, and Vinciguerra, Manlio

Abstract

Table S2. List of 599 transcripts displaying >1.5 fold change in hematopoietic progenitor cells (HPC) isolated from bone marrow of macroH2A1.1 KO versus Fl/Fl mice. (PDF 295 kb)

Published
2019
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26. International Prognostic Score (IPS-A) for Patients with Early Stage Chronic Lymphocytic Leukemia

Author

Condoluci, Adalgisa, primary, di Bergamo, Lodovico Terzi, additional, Langerbeins, Petra, additional, Hoechstetter, Manuela, additional, Herling, Carmen, additional, De Paoli, Lorenzo, additional, Delgado, Julio, additional, Rabe, Kari G., additional, Gentile, Massimo, additional, Doubek, Michael, additional, Mauro, Francesca Romana, additional, Chiodin, Giorgia, additional, Mattsson, Mattias, additional, Bahlo, Jasmin, additional, Cutrona, Giovanna, additional, Kotaskova, Jana, additional, Deambrogi, Clara, additional, Spina, Valeria, additional, Bruscaggin, Alessio, additional, Moia, Riccardo, additional, Bianchi, Elena, additional, Gerber, Bernhard, additional, Zucca, Emanuele, additional, Ghielmini, Michele, additional, Cavalli, Franco, additional, Stüssi, Georg, additional, Neri, Antonino, additional, Ferrarini, Manlio, additional, Rosenquist, Richard, additional, Forconi, Francesco, additional, Foà, Robin, additional, Pospisilova, Sarka, additional, Morabito, Fortunato, additional, Parikh, Sameer A., additional, Wierda, William G., additional, Montserrat, Emili, additional, Gaidano, Gianluca, additional, Hallek, Michael, additional, and Rossi, Davide, additional

Published
2019
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27. A Prognostic Tool for the Identification of Patients with Early Stage Chronic Lymphocytic Leukemia at Risk of Progression

Author

Condoluci, Adalgisa, primary, Terzi di Bergamo, Lodovico, additional, De Paoli, Lorenzo, additional, Delgado, Julio, additional, Gentile, Massimo, additional, Doubek, Michael, additional, Mauro, Francesca Romana, additional, Mattsson, Mattias, additional, Cutrona, Giovanna, additional, Kotaskova, Jana, additional, Deambrogi, Clara, additional, Gerber, Bernhard, additional, Spina, Valeria, additional, Bruscaggin, Alessio, additional, Zucca, Emanuele, additional, Cavalli, Franco, additional, Stuessi, Georg, additional, Neri, Antonino, additional, Ferrarini, Manlio, additional, Rosenquist, Richard, additional, Foà, Robin, additional, Pospisilova, Sarka, additional, Morabito, Fortunato, additional, Montserrat, Emili, additional, Gaidano, Gianluca, additional, Wierda, William G., additional, and Rossi, Davide, additional

Published
2018
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28. 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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29. Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations with other bio-markers and clinical impact

Author

Baliakas, Panagiotis, Jeronim, Sabine, Iskas, Michalis, Puiggros, Anna, Plevova, Karla, Xochelli, Aliki, Delgado, Julio, Kotaskova, Jana, Stalika, Evangelia, Costa, Pablo Abrisqueta, Durechova, Kristina, Papaioannou, Giorgos, Collado, Rosa, Doubek, Michael, Jose Calasanz, M., Ruiz-Xiville, Neus, Moreno, Carol, Anagnostopoulos, Achilles, Stavroyianni, Niki, Kater, Arnon, Espinet, Blanca, Sarka Pospisilova, Athanasiadou, Anastasia, Stamatopoulos, Kostas, and Haferlach, Claudia

Published
2017

30. Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia

Author

Baliakas, Panagiotis, primary, Moysiadis, Theodoros, additional, Hadzidimitriou, Anastasia, additional, Xochelli, Aliki, additional, Jeromin, Sabine, additional, Agathangelidis, Andreas, additional, Mattsson, Mattias, additional, Sutton, Lesley-Ann, additional, Minga, Eva, additional, Scarfò, Lydia, additional, Rossi, Davide, additional, Davis, Zadie, additional, Villamor, Neus, additional, Parker, Helen, additional, Kotaskova, Jana, additional, Stalika, Evangelia, additional, Plevova, Karla, additional, Mansouri, Larry, additional, Cortese, Diego, additional, Navarro, Alba, additional, Delgado, Julio, additional, Larrayoz, Marta, additional, Young, Emma, additional, Anagnostopoulos, Achilles, additional, Smedby, Karin E., additional, Juliusson, Gunnar, additional, Sheehy, Oonagh, additional, Catherwood, Mark, additional, Strefford, Jonathan C., additional, Stavroyianni, Niki, additional, Belessi, Chrysoula, additional, Pospisilova, Sarka, additional, Oscier, David, additional, Gaidano, Gianluca, additional, Campo, Elias, additional, Haferlach, Claudia, additional, Ghia, Paolo, additional, Rosenquist, Richard, additional, and Stamatopoulos, Kostas, additional

Published
2018
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31. CLL cells cumulate genetic aberrations prior to the first therapy even in outwardly inactive disease phase

Author

Hernández-Sánchez, María, primary, Kotaskova, Jana, additional, Rodríguez, Ana E, additional, Radova, Lenka, additional, Tamborero, David, additional, Abáigar, María, additional, Plevova, Karla, additional, Benito, Rocío, additional, Tom, Nikola, additional, Quijada-Álamo, Miguel, additional, Bikos, Vasileos, additional, Martín, Ana África, additional, Pal, Karol, additional, García de Coca, Alfonso, additional, Doubek, Michael, additional, López-Bigas, Nuria, additional, Hernández-Rivas, Jesús-María, additional, and Pospisilova, Sarka, additional

Published
2018
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32. Chronic lymphocytic leukemia: A prognostic model comprising only two biomarkers (IGHVmutational status and FISH cytogenetics) separates patients with different outcome and simplifies the CLL-IPI

Author

Delgado, Julio, primary, Doubek, Michael, additional, Baumann, Tycho, additional, Kotaskova, Jana, additional, Molica, Stefano, additional, Mozas, Pablo, additional, Rivas-Delgado, Alfredo, additional, Morabito, Fortunato, additional, Pospisilova, Sarka, additional, and Montserrat, Emili, additional

Published
2017
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34. Analysis of Clonal Evolution in Chronic Lymphocytic Leukemia from Inactive to Symptomatic Disease Prior Treatment Using Whole-Exome Sequencing

Author

Hernández-Sánchez, María, primary, Radova, Lenka, additional, Kotaskova, Jana, additional, Tamborero, David, additional, Rodriguez, Ana E, additional, Plevova, Karla, additional, Abáigar, María, additional, Bikos, Vasileios, additional, Benito, Rocío, additional, Takacova, Sylvia, additional, Quijada, Miguel, additional, Martín, Ana África, additional, Alcoceba, Miguel, additional, García de Coca, Alfonso, additional, Doubek, Michael, additional, González, Marcos, additional, Lopez-Bigas, Nuria, additional, Pospisilova, Sarka, additional, and Hernández-Rivas, Jesús María, additional

Published
2016
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35. Tailored Approaches for Refined Prognostication in Chronic Lymphocytic Leukemia Patients with Mutated Versus Unmutated Immunoglobulin Receptors

Author

Baliakas, Panagiotis, primary, Moysiadis, Theodoros, additional, Hadzidimitriou, Anastasia, additional, Xochelli, Aliki, additional, Mattsson, Mattias, additional, Sutton, Lesley-Ann, additional, Minga, Eva, additional, Scarfo, Lydia, additional, Rossi, Davide, additional, Davis, Zadie, additional, Agathangelidis, Andreas, additional, Villamor, Neus, additional, Parker, Helen, additional, Kotaskova, Jana, additional, Stalika, Evangelia, additional, Plevova, Karla, additional, Mansouri, Larry, additional, Cortese, Diego, additional, Lopez, Alba Navaro, additional, Delgado, Julio, additional, Larrayoz, Marta, additional, Young, Emma, additional, Anagnostopoulos, Achilles, additional, Smedby, Karin E, additional, Juliusson, Gunnar, additional, Catherwood, Mark, additional, Strefford, Jonathan C, additional, Stavroyianni, Niki, additional, Belessi, Chrysoula, additional, Pospisilova, Sarka, additional, Oscier, David, additional, Gaidano, Gianluca, additional, Campo, Elias, additional, Ghia, Paolo, additional, Rosenquist, Richard, additional, and Stamatopoulos, on behalf of ERIC, Kostas, additional

Published
2016
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36. 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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37. 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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39. 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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42. 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

Kotaskova, Jana, Tichy, Boris, Trbusek, Martin, Francova, Hana Skuhrova, Kabathova, Jitka, Malcikova, Jitka, Doubek, Michael, Brychtova, Yvona, Mayer, Jiri, and Pospisilova, Sarka

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 IGHVstatus in CLL cells. We analyzed a cohort of 118 CLL patients with different IGHVmutational 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: LAG3high 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 IGHVwith 90% specificity (P< 0.0001). Moreover, high expression of tested gene-set and unmutated IGHVequally correlated with reduced treatment-free survival (P= 7.7 * 10−11vs. P= 1.8 * 10−11). Our results suggest that IGHV status can be precisely assessed using the expression analysis of LAG3, LPL, and ZAP70genes. 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
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43. Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY

Author

Mansouri, Larry, Thorvaldsdottir, Birna, Sutton, Lesley-Ann, Karakatsoulis, Georgios, Meggendorfer, Manja, Parker, Helen, Nadeu, Ferran, Brieghel, Christian, Laidou, Stamatia, Moia, Riccardo, Rossi, Davide, Catherwood, Mark, Kotaskova, Jana, Delgado, Julio, Rodríguez-Vicente, Ana E., Benito, Rocío, Rigolin, Gian Matteo, Bonfiglio, Silvia, Scarfo, Lydia, Mattsson, Mattias, Davis, Zadie, Gogia, Ajay, Rani, Lata, Baliakas, Panagiotis, Foroughi-Asl, Hassan, Jylhä, Cecilia, Skaftason, Aron, Rapado, Inmaculada, Miras, Fatima, Martinez-Lopez, Joaquín, de la Serna, Javier, Rivas, Jesús María Hernández, Thornton, Patrick, Larráyoz, María José, Calasanz, M.J, Fésüs, Viktória, Mátrai, Zoltán, Bödör, Csaba, Smedby, Karin E., Espinet, Blanca, Puiggros, Anna, Gupta, Ritu, Bullinger, Lars, Bosch José, Francesc Xavier, Tazón-Vega, Bárbara, Baran-Marszak, Fanny, Oscier, David, Nguyen-Khac, Florence, Zenz, Thorsten, Terol, Maria Jose, Cuneo, Antonio, Hernández-Sánchez, María, Pospisilova, Sarka, Mills, Ken, Gaidano, Gianluca, Niemann, Carsten U., Campo, Elias, Strefford, Jonathan C., Ghia, Paolo, Stamatopoulos, Kostas, Rosenquist, Richard, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Mansouri L, Thorvaldsdottir B, Sutton LA] Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. [Karakatsoulis G] Centre for Research and Technology Hellas, Institute of Applied Biosciences, Thessaloniki, Greece. Department of Mathematics, University of Ioannina, Ioannina, Greece. [Meggendorfer M] MLL Munich Leukemia Laboratory, Munich, Germany. [Parker H] Cancer Genomics, School for Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK. [Bosch F, Tazón-Vega B] Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain, Vall d'Hebron Barcelona Hospital Campus, Karolinska Institutet [Stockholm], Institute of Applied Biosciences [Thessaloniki, Greece] (IAB), University of Ioannina, Munich Leukemia Laboratory [Munich, Germany] (M2L), University of Southampton, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Copenhagen University Hospital, Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO), Oncology Institute of Southern Switzerland (IOSI), Institute Of Oncology Research [Bellinzona, Switzerland] (IOL), Queen's University [Belfast] (QUB), University Hospital Brno, Masaryk University [Brno] (MUNI), Clinic Barcelona Hospital Universitari, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Università degli Studi di Ferrara = University of Ferrara (UniFE), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Uppsala University, University Hospitals Dorset NHS Foundation Trust [Bournemouth, UK] (UHD), All India Institute of Medical Sciences [New Delhi], Hospital Universitario 12 de Octubre [Madrid], Spanish National Cancer Research Center (CNIO), Hôpital de Beaumont [Dublin, Ireland] (HB), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA), Navarra Institute for Health Research / Instituto de Investigación Sanitaria de Navarra (IdiSNA), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA)-Universidad de Navarra [Pamplona] (UNAV)-Clínica Universidad de Navarra [Pamplona], Semmelweis University [Budapest], South-Pest Hospital Centre [Budapest, Hungary] (SPHC), IMIM-Hospital del Mar, Generalitat de Catalunya, Humboldt University Of Berlin, Universitat Autònoma de Barcelona (UAB), Adaptateurs de signalisation en hématologie (ASIH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Hôpital Avicenne HUPSSD - Service d'Hématologie Biologique, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universität Zürich [Zürich] = University of Zurich (UZH), University hospital of Zurich [Zurich], Universitat de València (UV), Centre for Research and Technology Hellas (CERTH), Karolinska University Hospital [Stockholm], and Baran-Marszak, Fanny

Subjects
Cancer Research, Otros calificadores::Otros calificadores::/genética [Otros calificadores], [SDV]Life Sciences [q-bio], Leucèmia limfocítica crònica - Aspectes genètics, Genetic Phenomena::Genetic Variation::Mutation [PHENOMENA AND PROCESSES], Hematology, [SDV] Life Sciences [q-bio], Anomalies cromosòmiques, Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Lymphoid::Leukemia, B-Cell::Leukemia, Lymphocytic, Chronic, B-Cell [DISEASES], Oncology, Genetics research, Other subheadings::Other subheadings::/genetics [Other subheadings], Cancer genetics, fenómenos genéticos::variación genética::mutación [FENÓMENOS Y PROCESOS], neoplasias::neoplasias por tipo histológico::leucemia::leucemia linfoide::leucemia de células B::leucemia linfocítica crónica de células B [ENFERMEDADES]
Abstract

Cancer genetics; Genetics research Genètica del càncer; Recerca genètica Genética del cáncer; Investigación genética 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. The European Research Initiative on CLL (ERIC) is a partner in the HARMONY Alliance, the EHA Scientific Working group on CLL and the ELN Workpackage 7 on CLL. This work was in part supported by; Associazione Italiana per la Ricerca sul Cancro—AIRC, Milano, Italy (Investigator Grant #20246 and Special Program on Metastatic Disease—5 per mille #21198); ERA NET TRANSCAN-2 Joint Transnational Call for Proposals: JTC 2014 (project #143 GCH-CLL) and JTC 2016 (project #179 NOVEL), project code (MIS) 5041673; Bando della Ricerca Finalizzata 2018, Ministero della Salute, Roma, Italy (progetto RF-2018–12368231); “la Caixa” Foundation (Health Research 2017 Program HR17-00221); the American Association for Cancer Research (2021 AACR-Amgen Fellowship in Clinical/Translational Cancer Research, 21-40-11-NADE), the European Hematology Association (EHA Junior Research Grant 2021, RG-202012-00245), and the Lady Tata Memorial Trust (International Award for Research in Leukaemia 2021-2022, LADY_TATA_21_3223); the Hellenic Precision Medicine Network in Oncology; project ODYSSEAS (Intelligent and Automated Systems for enabling the Design, Simulation and Development of Integrated Processes and Products) implemented under the “Action for the Strategic Development on the Research and Technological Sector”, funded by the Operational Programme “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014-2020) and co-financed by Greece and the European Union, with grant agreement no: MIS 5002462”; MH CZ—DRO (FNBr, 65269705), NV19-03-00091 and the project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102)—Funded by the European Union—Next-Generation EU; Instituto de Salud Carlos III (ISCIII), “PI21/00983”, co-funded by the European Union; the EU’s Horizon 2020 research and innovation program under grant agreement No. 739593, by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, financed under the K21_137948, FK20_134253, TKP2021-EGA-24 and TKP2021-NVA-15 funding schemes, and Elixir Hungary; Instituto de Salud Carlos III (ISCIII), “PI21/00983”, co-funded by the European Union; Fondo di Ateneo per la Ricerca (FAR) 2019, 2020 and 2021 of the University of Ferrara (GMR; AC), Associazione Italiana contro le Leucemie-Linfomi e Mieloma ONLUS Ferrara (AC; GMR), BEAT Leukemia Foundation Milan Italy (AC); the Danish Cancer Society and the CLL-CLUE project under the frame of ERA PerMed; Cancer Research UK (ECRIN-M3 accelerator award C42023/A29370, Southampton Experimental Cancer Medicine Centre grant C24563/A15581, Cancer Research UK Southampton Centre grant C34999/A18087, and programme C2750/A23669); the Swedish Cancer Society (19 0425 Pj 01 H), the Swedish Research Council (2020-01750), the Knut and Alice Wallenberg Foundation (2016.0373), Region Stockholm (ALF/FoUI-962423), and Radiumhemmets Forskningsfonder (194133), Stockholm; and Lion’s Cancer Research Foundation, Uppsala.

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44. 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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48. CLL: A Prognostic Model Comprising Only Two Biomarkers (IGHVMutational Status and FISH-Cytogenetics) Separates Patients with Different Prognosis and Simplifies the CLL-IPI.

Author

Delgado, Julio, Doubek, Michael, Baumann, Tycho, Kotaskova, Jana, Mozas, Pablo, Rivas-Delgado, Alfredo, Pospisilova, Sarka, and Montserrat, Emili

Abstract

Background: Survival of pts with chronic lymphocytic leukemia (CLL) ranges from a few years to a normal lifespan. Clinical stages (i.e. Rai, Binet) are the basis for CLL prognostication but do not reflect the complex biology of CLL, which ultimately shapes the disease heterogeneity. Recently, a CLL-International Prognostic Index (CLL-IPI) which includes five clinical and biological variables (i.e. age, IGHVmutational status, del(17p), beta2-microglobulin [B2M] and Rai or Binet stages) and stratifies pts into four different categories has been proposed. This prognostic index is obtained by the sum of the score given to each parameter and includes dichotomized continuous variables. The aim of this study was to determine whether a prognostic model based only on biomarkers could separate CLL patients with different outcomes and simplify the CLL-IPI.

Published
2016
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49. High Expression of LAG3, LPL and ZAP-70 Genes in B-CLL Strongly Correlates with Unmutated IgVHand Early Therapy Requirement.

Author

Kotaskova, Jana, Mraz, Marek, Tichy, Boris, Kabathova, Jitka, Malcikova, Jitka, Trbusek, Martin, Francova, Hana, Doubek, Michael, Brychtova, Yvona, Mayer, Jiri, and Pospisilova, Sarka

Abstract

Mutational status of immunoglobulin genes coding for heavy chain variable region (IgVH) stratifies patients with B-cell chronic lymphocytic leukemia (CLL) into two distinct prognostic groups. Expression level of specific genes such as LPL, ZAP-70, ADAM29 or CLLU1 has previously been shown to distinguish these two subgroups, although their exact role in CLL pathogenesis remains unclear. In our study we performed microarray and Real-time PCR analyses of gene expression in B-CLL cells with different IgVHmutational status in an attempt to further identify potential discriminating genes. Heparinised peripheral blood samples were collected from 92 previously untreated B-CLL patients (40 IgVHunmutated vs. 52 IgVHmutated) with a median age of 62 years (ranging from 40 to 81 years). B-cells were separated using cocktails of selected bispecific antibodies directed against cell surface antigens of hematopoietic cells and glycophorin A (RosetteSep® B Cell Enrichment Kit, StemCell Technologies). Great attention was paid to T-cell depletion using Human CD3 Depletion Cocktail. Samples with lower percentage of B-CLL cells were further processed by immunomagnetic separation (EasySep® FITC Selection Cocktail, anti-CD5FITC) and only samples with B-CLL cell content higher than 95 % (assessed using flow cytometry) were used for the gene expression analysis. Microarray gene expression analysis of 20 B-CLL patients (10 with mutated and 10 with unmutated IgVH) was performed using Agilent Human 1A Arrays and obtained data were statistically analysed using SAM (Significance Analysis of Microarrays). Among approx. 50 diferentially expressed genes, high expression of LPL and LAG3 (Lymphocyte- Activation Gene 3) was the most prominently associated with unmutated IgVHsubtype. The mRNA levels of selected genes (LAG3, LPL, ZAP-70, AICDA, BCL2, CLLU1, TCF7, SEPT10, ADAM29) were further tested on a cohort of 92 B-CLL patients using quantitative RT-PCR (TaqMan® Gene Expression Assay, Applied Biosystems). Among them, LAG3, LPL and ZAP-70 reached the best statistical significance (p-value < 0.001; Wilcoxon's rank-sum test). LAG3 expression level can predict unmutated IgVHwith 100% sensitivity and could be used as a novel potential CLL prognostic marker. LAG3 plays role in T-cell dependent B-cell activation during affinity maturation and its over-expression in cells with unmutated IgVHmay be a consequence of improper signalling in this process. Combination of expression data of three genes LAG3, LPL and ZAP-70 reliably assigned 95% of CLL samples into a correct IgVHsubtype and seems to be better predictor of IgVH status than either of these genes itself. Moreover, we have analysed the correlation between expression of those three IgVHsurrogate markers and necessity of therapeutical intervention. The patients manifesting high expression of LAG3, LPL and ZAP-70 required therapy significantly earlier than patients with low expression of those genes as calculated by Kaplan-Meier estimator (median time to the first therapy was 797 days in patients with high expression of surrogate markers, median was not reached in patients with low expression of surrogate markers). Differences of time to the first therapy between patients with differential expression of three IgVHsurrogate markers (p=4.4*10−8, log-rank test) and differences between patients with different IgVHstatus (p=7.5*10−8, log-rank test) showed high significance. These results suggest that IgVHstatus could be precisely assessed using expression analysis of three genes LAG3, LPL and ZAP-70. The expression data of those surrogate markers provide even better statistical concordance with time to requirement of the first therapy than IgVHmutational status itself and possibly could be used in the diagnostics.

Published
2008
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50. Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia

Author

Zadie Davis, Richard Rosenquist, Chrysoula Belessi, Panagiotis Baliakas, Niki Stavroyianni, Theodoros Moysiadis, Elias Campo, Julio Delgado, Šárka Pospíšilová, Kostas Stamatopoulos, Marta Larrayoz, Davide Rossi, Jonathan C. Strefford, Larry Mansouri, Achilles Anagnostopoulos, Mattias Mattsson, Karin E. Smedby, Diego Cortese, Anastasia Hadzidimitriou, Lesley-Ann Sutton, Neus Villamor, David Oscier, Alba Navarro, Jana Kotašková, Evangelia Stalika, Gianluca Gaidano, Karla Plevová, Mark Catherwood, Gunnar Juliusson, Paolo Ghia, Sabine Jeromin, Oonagh Sheehy, Lydia Scarfò, Andreas Agathangelidis, Emma Young, Helen Parker, Eva Minga, Aliki Xochelli, Claudia Haferlach, Baliakas, Panagioti, Moysiadis, Theodoro, Hadzidimitriou, Anastasia, Xochelli, Aliki, Jeromin, Sabine, Agathangelidis, Andrea, Mattsson, Mattia, Sutton, Lesley-Ann, Minga, Eva, Scarfò, Lydia, Rossi, Davide, Davis, Zadie, Villamor, Neu, Parker, Helen, Kotaskova, Jana, Stalika, Evangelia, Plevova, Karla, Mansouri, Larry, Cortese, Diego, Navarro, Alba, Delgado, Julio, Larrayoz, Marta, Young, Emma, Anagnostopoulos, Achille, Smedby, Karin E., Juliusson, Gunnar, Sheehy, Oonagh, Catherwood, Mark, Strefford, Jonathan C., Stavroyianni, Niki, Belessi, Chrysoula, Pospisilova, Sarka, Oscier, David, Gaidano, Gianluca, Campo, Elia, Haferlach, Claudia, Ghia, Paolo, Rosenquist, Richard, Stamatopoulos, Kostas, and Universitat de Barcelona

Subjects
Male, Oncology, medicine.medical_specialty, Pronòstic mèdic, Chronic lymphocytic leukemia, Somatic hypermutation, Relative weight, Kaplan-Meier Estimate, Immunogenetics, Article, Time-to-Treatment, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, hemic and lymphatic diseases, Biomarkers, Tumor, medicine, Humans, Chronic Lymphocytic Leukemia, Leucèmia limfocítica crònica, Hematologi, Aged, Neoplasm Staging, 030304 developmental biology, Aged, 80 and over, Chromosome Aberrations, 0303 health sciences, Hematology, biology, business.industry, medicine.disease, Prognosis, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Leukemia, 030220 oncology & carcinogenesis, Mutation, biology.protein, Female, Disease Susceptibility, Antibody, business, Trisomy
Abstract

Chronic lymphocytic leukemia patients with differential somatic hypermutation status of the immunoglobulin heavy variable genes, namely mutated or unmutated, display fundamental clinicobiological differences. Considering this, we assessed prognosis separately within mutated and unmutated chronic lymphocytic leukemia in 3015 patients, hypothesizing that the relative significance of relevant indicators may differ between these two categories. Within Binet-A mutated chronic lymphocytic leukemia 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 5- and 10-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 unmutated chronic lymphocytic leukemia patients, besides TP53 abnormalities, del(11q) and/or SF3B1 mutations were associated with the shortest time-to-first-trearment (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 chronic lymphocytic leukemia 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 chronic lymphocytic leukemia.

Published
2019

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