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21 results on '"Francova, Hana Skuhrova"'

1. Molecular Evidence for Antigen Drive in the Natural History of Mantle Cell Lymphoma

Author

Xochelli, Aliki, Sutton, Lesley-Ann, Agathangelidis, Andreas, Stalika, Evangelia, Karypidou, Maria, Marantidou, Fotini, Lopez, Alba Navarro, Papadopoulos, Giorgos, Supikova, Jana, Groenen, Patricia, Boudjogra, Myriam, Sundstrom, Christer, Ponzoni, Maurilio, Francova, Hana Skuhrova, Anagnostopoulos, Achilles, Pospisilova, Sarka, Papadaki, Theodora, Tzovaras, Dimitris, Ghia, Paolo, Pott, Christiane, Davi, Frederic, Campo, Elias, Rosenquist, Richard, Hadzidimitriou, Anastasia, Belessi, Chrysoula, and Stamatopoulos, Kostas

Published
2015
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2. Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study

Author

Baliakas, Panagiotis, Hadzidimitriou, Anastasia, Sutton, Lesley-Ann, Minga, Eva, Agathangelidis, Andreas, Nichelatti, Michele, Tsanousa, Athina, Scarfò, Lydia, Davis, Zadie, Yan, Xiao-Jie, Shanafelt, Tait, Plevova, Karla, Sandberg, Yorick, Vojdeman, Fie Juhl, Boudjogra, Myriam, Tzenou, Tatiana, Chatzouli, Maria, Chu, Charles C, Veronese, Silvio, Gardiner, Anne, Mansouri, Larry, Smedby, Karin E, Pedersen, Lone Bredo, van Lom, Kirsten, Giudicelli, Véronique, Francova, Hana Skuhrova, Nguyen-Khac, Florence, Panagiotidis, Panagiotis, Juliusson, Gunnar, Angelis, Lefteris, Anagnostopoulos, Achilles, Lefranc, Marie-Paule, Facco, Monica, Trentin, Livio, Catherwood, Mark, Montillo, Marco, Geisler, Christian H, Langerak, Anton W, Pospisilova, Sarka, Chiorazzi, Nicholas, Oscier, David, Jelinek, Diane F, Darzentas, Nikos, Belessi, Chrysoula, Davi, Frederic, Rosenquist, Richard, Ghia, Paolo, and Stamatopoulos, Kostas

Published
2014
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6. Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL

Author

Agathangelidis, Andreas, Chatzidimitriou, Anastasia, Gemenetzi, Katerina, Giudicelli, Veronique, Karypidou, Maria, Plevova, Karla, Davis, Zadie, Yan, Xiao-Jie, Jeromin, Sabine, Schneider, Christof, Pedersen, Lone Bredo, Tschumper, Renee C., Sutton, Lesley-Ann, Baliakas, Panagiotis, Scarfo, Lydia, van Gastel, Ellen J., Armand, Marine, Tausch, Eugen, Biderman, Bella, Baer, Constance, Bagnara, Davide, Navarro, Alba, de Septenville, Anne Langlois, Guido, Valentina, Mitterbauer-Hohendanner, Gerlinde, Dimovski, Aleksandar, Brieghel, Christian, Lawless, Sarah, Meggendorfer, Manja, Brazdilova, Kamila, Ritgen, Matthias, Facco, Monica, Tresoldi, Cristina, Visentin, Andrea, Patriarca, Andrea, Catherwood, Mark, Bonello, Lisa, Sudarikov, Andrey, Vanura, Katrina, Roumelioti, Maria, Francova, Hana Skuhrova, Moysiadis, Theodoros, Veronese, Silvio, Giannopoulos, Krzysztof, Mansouri, Larry, Karan-Djurasevic, Teodora, Sandaltzopoulos, Raphael, Bodor, Csaba, Fais, Franco, Kater, Arnon, Panovska, Irina, Rossi, Davide, Alshemmari, Salem, Panagiotidis, Panagiotis, Costeas, Paul, Espinet, Blanca, Antic, Darko, Foroni, Letizia, Montillo, Marco, Trentin, Livio, Stavroyianni, Niki, Gaidano, Gianluca, di Celle, Paola Francia, Niemann, Carsten, Campo, Elias, Anagnostopoulos, Achilles, Pott, Christiane, Fischer, Kirsten, Hallek, Michael, Oscier, David, Stilgenbauer, Stephan, Haferlach, Claudia, Jelinek, Diane, Chiorazzi, Nicholas, Pospisilova, Sarka, Lefranc, Marie-Paule, Kossida, Sofia, Langerak, Anton W., Belessi, Chrysoula, Davi, Frederic, Rosenquist, Richard, Ghia, Paolo, Stamatopoulos, Kostas, Agathangelidis, Andreas, Chatzidimitriou, Anastasia, Gemenetzi, Katerina, Giudicelli, Veronique, Karypidou, Maria, Plevova, Karla, Davis, Zadie, Yan, Xiao-Jie, Jeromin, Sabine, Schneider, Christof, Pedersen, Lone Bredo, Tschumper, Renee C., Sutton, Lesley-Ann, Baliakas, Panagiotis, Scarfo, Lydia, van Gastel, Ellen J., Armand, Marine, Tausch, Eugen, Biderman, Bella, Baer, Constance, Bagnara, Davide, Navarro, Alba, de Septenville, Anne Langlois, Guido, Valentina, Mitterbauer-Hohendanner, Gerlinde, Dimovski, Aleksandar, Brieghel, Christian, Lawless, Sarah, Meggendorfer, Manja, Brazdilova, Kamila, Ritgen, Matthias, Facco, Monica, Tresoldi, Cristina, Visentin, Andrea, Patriarca, Andrea, Catherwood, Mark, Bonello, Lisa, Sudarikov, Andrey, Vanura, Katrina, Roumelioti, Maria, Francova, Hana Skuhrova, Moysiadis, Theodoros, Veronese, Silvio, Giannopoulos, Krzysztof, Mansouri, Larry, Karan-Djurasevic, Teodora, Sandaltzopoulos, Raphael, Bodor, Csaba, Fais, Franco, Kater, Arnon, Panovska, Irina, Rossi, Davide, Alshemmari, Salem, Panagiotidis, Panagiotis, Costeas, Paul, Espinet, Blanca, Antic, Darko, Foroni, Letizia, Montillo, Marco, Trentin, Livio, Stavroyianni, Niki, Gaidano, Gianluca, di Celle, Paola Francia, Niemann, Carsten, Campo, Elias, Anagnostopoulos, Achilles, Pott, Christiane, Fischer, Kirsten, Hallek, Michael, Oscier, David, Stilgenbauer, Stephan, Haferlach, Claudia, Jelinek, Diane, Chiorazzi, Nicholas, Pospisilova, Sarka, Lefranc, Marie-Paule, Kossida, Sofia, Langerak, Anton W., Belessi, Chrysoula, Davi, Frederic, Rosenquist, Richard, Ghia, Paolo, and Stamatopoulos, Kostas

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed satellites, were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL.

Published
2021

7. The frequency of TP53 gene defects differs between chronic lymphocytic leukaemia subgroups harbouring distinct antigen receptors

Author

Malcikova, Jitka, Stalika, Evangelia, Davis, Zadie, Plevova, Karla, Trbusek, Martin, Mansouri, Larry, Scarfò, Lydia, Baliakas, Panagiotis, Gardiner, Anne, Sutton, Lesley-Ann, Francova, Hana Skuhrova, Agathangelidis, Andreas, Anagnostopoulos, Achilles, Tracy, Ian, Makris, Antonis, Smardova, Jana, Ghia, Paolo, Belessi, Chrysoula, Gonzalez, David, Rosenquist, Richard, Oscier, David, Pospisilova, Sarka, and Stamatopoulos, Kostas

Published
2014
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8. Profiling of biological and environmental risk factors in immunogenetic subgroups of chronic lymphocytic leukemia - Czech national study.

Author

Stranska, Kamila, Plevova, Karla, Francova, Hana Skuhrova, Skabrahova, Hana, von Jagwitz-Biegnitz, Magdalena, Radova, Lenka, Panovska, Anna, Hrobkova, Stanislava, Brychtova, Yvona, Urbanova, Renata, Smolej, Lukas, Simkovic, Martin, Zuchnicka, Jana, Mohammadova, Lekaa, Spacek, Martin, Mayer, Jiri, Pospisilova, Sarka, and Doubek, Michael

Abstract

Aims. This is a nation-wide survey of chronic lymphocytic leukemia (CLL) patients at six large hematology centers in the Czech Republic. The aim was to identify specific populations, social, and health characteristics of CLL subgroups divided according to the immunogenetic features of their B cell receptors (BCRs) and clonality. Patients and Methods. Questionnaires directed to specific health, social, and environmental conditions were collected in a cohort of 573 CLL patients. For these patients, immunoglobulin heavy chain gene rearrangements were also analyzed in order to gain information about their clonality, IGHV mutational status, and the presence of stereotyped BCRs. Data extracted from the questionnaires were analyzed statistically in the context of immunogenetic features of the cohort. Results. There were no statistically significant differences in the data collected in the survey between patients with mutated and patients with unmutated IGHV. However, patients with oligoclonal CLL reported health conditions such as hypercholesterolemia, hypertension, herpes simplex, tumors, and also, separately, CLL in 1st degree relatives, more often than their monoclonal counterparts. In patients with stereotyped BCRs, we found more frequent alcohol consumption and gastric infections in subset #1 cases and frequent cholecystectomies and familial CLL in subset #2 cases. Conclusion. To the best of our knowledge, this study is the first to investigate CLL immunogenetic features and clonality in the context of epidemiological data. We reported statistically significant associations suggesting the influence of certain health and social conditions on a number of clonal populations expanding in CLL and also on characteristic BCR features, especially stereotypy. [ABSTRACT FROM AUTHOR]

Published
2020
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9. Not all IGHV3-21 chronic lymphocytic leukemias are equal: prognostic considerations

Author

Baliakas, Panagiotis, Agathangelidis, Andreas, Hadzidimitriou, Anastasia, Sutton, Lesley-Ann, Minga, Eva, Tsanousa, Athina, Scarfò, Lydia, Davis, Zadie, Yan, Xiao-Jie, Shanafelt, Tait, Plevova, Karla, Sandberg, Yorick, Vojdeman, Fie Juhl, Boudjogra, Myriam, Tzenou, Tatiana, Chatzouli, Maria, Chu, Charles C., Veronese, Silvio, Gardiner, Anne, Mansouri, Larry, Smedby, Karin E., Pedersen, Lone Bredo, Moreno, Denis, Van Lom, Kirsten, Giudicelli, Véronique, Francova, Hana Skuhrova, Nguyen-Khac, Florence, Panagiotidis, Panagiotis, Juliusson, Gunnar, Angelis, Lefteris, Anagnostopoulos, Achilles, Lefranc, Marie-Paule, Facco, Monica, Trentin, Livio, Catherwood, Mark, Montillo, Marco, Geisler, Christian H., Langerak, Anton W., Pospisilova, Sarka, Chiorazzi, Nicholas, Oscier, David, Jelinek, Diane F., Darzentas, Nikos, Belessi, Chrysoula, Davi, Frederic, Ghia, Paolo, Rosenquist, Richard, and Stamatopoulos, Kostas

Published
2015
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10. Single cell analysis revealed a coexistence of NOTCH1 and TP53 mutations within the same cancer cells in chronic lymphocytic leukaemia patients

Author

Kantorova, Barbara, primary, Malcikova, Jitka, additional, Brazdilova, Kamila, additional, Borsky, Marek, additional, Plevova, Karla, additional, Smardova, Jana, additional, Radova, Lenka, additional, Tom, Nikola, additional, Trbusek, Martin, additional, Diviskova, Eva, additional, Francova, Hana Skuhrova, additional, Navrkalova, Veronika, additional, Doubek, Michael, additional, Brychtova, Yvona, additional, Mayer, Jiri, additional, and Pospisilova, Sarka, additional

Published
2016
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11. Not all IGHV3-21 chronic lymphocytic leukemias are equal:prognostic considerations

Author

Baliakas, Panagiotis, Agathangelidis, Andreas, Hadzidimitriou, Anastasia, Sutton, Lesley-Ann, Minga, Eva, Tsanousa, Athina, Scarfò, Lydia, Davis, Zadie, Yan, Xiao-Jie, Shanafelt, Tait, Plevova, Karla, Sandberg, Yorick, Vojdeman, Fie Juhl, Boudjogra, Myriam, Tzenou, Tatiana, Chatzouli, Maria, Chu, Charles C, Veronese, Silvio, Gardiner, Anne, Mansouri, Larry, Smedby, Karin E, Pedersen, Lone Bredo, Moreno, Denis, Van Lom, Kirsten, Giudicelli, Véronique, Francova, Hana Skuhrova, Nguyen-Khac, Florence, Panagiotidis, Panagiotis, Juliusson, Gunnar, Angelis, Lefteris, Anagnostopoulos, Achilles, Lefranc, Marie-Paule, Facco, Monica, Trentin, Livio, Catherwood, Mark, Montillo, Marco, Geisler, Christian H, Langerak, Anton W, Pospisilova, Sarka, Chiorazzi, Nicholas, Oscier, David, Jelinek, Diane F, Darzentas, Nikos, Belessi, Chrysoula, Davi, Frederic, Ghia, Paolo, Rosenquist, Richard, Stamatopoulos, Kostas, Baliakas, Panagiotis, Agathangelidis, Andreas, Hadzidimitriou, Anastasia, Sutton, Lesley-Ann, Minga, Eva, Tsanousa, Athina, Scarfò, Lydia, Davis, Zadie, Yan, Xiao-Jie, Shanafelt, Tait, Plevova, Karla, Sandberg, Yorick, Vojdeman, Fie Juhl, Boudjogra, Myriam, Tzenou, Tatiana, Chatzouli, Maria, Chu, Charles C, Veronese, Silvio, Gardiner, Anne, Mansouri, Larry, Smedby, Karin E, Pedersen, Lone Bredo, Moreno, Denis, Van Lom, Kirsten, Giudicelli, Véronique, Francova, Hana Skuhrova, Nguyen-Khac, Florence, Panagiotidis, Panagiotis, Juliusson, Gunnar, Angelis, Lefteris, Anagnostopoulos, Achilles, Lefranc, Marie-Paule, Facco, Monica, Trentin, Livio, Catherwood, Mark, Montillo, Marco, Geisler, Christian H, Langerak, Anton W, Pospisilova, Sarka, Chiorazzi, Nicholas, Oscier, David, Jelinek, Diane F, Darzentas, Nikos, Belessi, Chrysoula, Davi, Frederic, Ghia, Paolo, Rosenquist, Richard, and Stamatopoulos, Kostas

Abstract

An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset #2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue in 8593 CLL patients of whom 437 (5%) used the IGHV3-21 gene with 254/437 (58%) classified as subset #2. Within subset #2, immunoglobulin heavy variable (IGHV)-mutated cases predominated, whereas non-subset #2/IGHV3-21 was enriched for IGHV-unmutated cases (P = .002). Subset #2 exhibited significantly shorter time-to-first-treatment (TTFT) compared with non-subset #2/IGHV3-21 (22 vs 60 months, P = .001). No such difference was observed between non-subset #2/IGHV3-21 vs the remaining CLL with similar IGHV mutational status. In conclusion, IGHV3-21 CLL should not be axiomatically considered a homogeneous entity with adverse prognosis, given that only subset #2 emerges as uniformly aggressive, contrasting non-subset #2/IGVH3-21 patients whose prognosis depends on IGHV mutational status as the remaining CLL.

Published
2015

12. The frequency ofTP53gene defects differs between chronic lymphocytic leukaemia subgroups harbouring distinct antigen receptors

Author

Malcikova, Jitka, primary, Stalika, Evangelia, additional, Davis, Zadie, additional, Plevova, Karla, additional, Trbusek, Martin, additional, Mansouri, Larry, additional, Scarfò, Lydia, additional, Baliakas, Panagiotis, additional, Gardiner, Anne, additional, Sutton, Lesley-Ann, additional, Francova, Hana Skuhrova, additional, Agathangelidis, Andreas, additional, Anagnostopoulos, Achilles, additional, Tracy, Ian, additional, Makris, Antonis, additional, Smardova, Jana, additional, Ghia, Paolo, additional, Belessi, Chrysoula, additional, Gonzalez, David, additional, Rosenquist, Richard, additional, Oscier, David, additional, Pospisilova, Sarka, additional, and Stamatopoulos, Kostas, additional

Published
2014
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13. High Expression of Activation-Induced Cytidine Deaminase and in Vivo Class Switch Recombination in Mantle Cell Lymphoma : Further Support for Antigen Involvement in Lymphomagenesis

Author

Xochelli, Aliki, Marantidou, Fotini, Stalika, Evangelia, Sutton, Lesley-Ann, Navarro, Alba, Supikova, Jana, Karypidis, Kyriakos, Chatzouli, Maria, Boudjogra, Myriam, Sundström, Christer, Francova, Hana Skuhrova, Anagnostopoulos, Achilles, Pospisilova, Sarka, Papadaki, Theodora, Pott, Christiane, Davi, Frederic, Campo, Elias, Rosenquist, Richard, Belessi, Chrysoula, Stamatopoulos, Kostas, Xochelli, Aliki, Marantidou, Fotini, Stalika, Evangelia, Sutton, Lesley-Ann, Navarro, Alba, Supikova, Jana, Karypidis, Kyriakos, Chatzouli, Maria, Boudjogra, Myriam, Sundström, Christer, Francova, Hana Skuhrova, Anagnostopoulos, Achilles, Pospisilova, Sarka, Papadaki, Theodora, Pott, Christiane, Davi, Frederic, Campo, Elias, Rosenquist, Richard, Belessi, Chrysoula, and Stamatopoulos, Kostas

Published
2012

14. High Expression of Activation-Induced Cytidine Deaminase and in Vivo Class Switch Recombination in Mantle Cell Lymphoma: Further Support for Antigen Involvement in Lymphomagenesis

Author

Xochelli, Aliki, primary, Marantidou, Fotini, additional, Stalika, Evangelia, additional, Sutton, Lesley-Ann, additional, Navarro, Alba, additional, Supikova, Jana, additional, Karypidis, Kyriakos, additional, Chatzouli, Maria, additional, Boudjogra, Myriam, additional, Sundstrom, Christer, additional, Francova, Hana Skuhrova, additional, Anagnostopoulos, Achilles, additional, Pospisilova, Sarka, additional, Papadaki, Theodora, additional, Pott, Christiane, additional, Davi, Frederic, additional, Campo, Elias, additional, Rosenquist, Richard, additional, Belessi, Chrysoula, additional, and Stamatopoulos, Kostas, additional

Published
2012
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15. Fludarabine with cytarabine followed by reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation in patients with poor-risk chronic lymphocytic leukemia

Author

Krejci, Marta, primary, Doubek, Michael, additional, Brychtova, Yvona, additional, Stehlikova, Olga, additional, Chovancova, Jana, additional, Tichy, Boris, additional, Francova, Hana Skuhrova, additional, Navratil, Milan, additional, Tomiska, Miroslav, additional, Horky, Ondrej, additional, Pospisilova, Sarka, additional, and Mayer, Jiri, additional

Published
2012
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16. 5.7 The Impact of Specific Mutations in TP53 Gene on the Results of Alemtuzumab Therapy in CLL Patients

Author

Doubek, Michael, primary, Trbusek, Martin, additional, Malcikova, Jitka, additional, Brychtova, Yvona, additional, Smardova, Jana, additional, Lochmanova, Jana, additional, Panovska, Anna, additional, Francova, Hana Skuhrova, additional, Mraz, Marek, additional, Tichy, Boris, additional, Sebejova, Ludmila, additional, Dobes, Petr, additional, Plevova, Karla, additional, Vankova, Gabriela, additional, Kuglik, Petr, additional, Mayer, Jiri, additional, and Pospisilova, Sarka, additional

Published
2011
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18. Missense Mutations Located in Structural p53 DNA-Binding Motifs Are Associated With Extremely Poor Survival in Chronic Lymphocytic Leukemia

Author

Trbusek, Martin, primary, Smardova, Jana, additional, Malcikova, Jitka, additional, Sebejova, Ludmila, additional, Dobes, Petr, additional, Svitakova, Miluse, additional, Vranova, Vladimira, additional, Mraz, Marek, additional, Francova, Hana Skuhrova, additional, Doubek, Michael, additional, Brychtova, Yvona, additional, Kuglik, Petr, additional, Pospisilova, Sarka, additional, and Mayer, Jiri, additional

Published
2011
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20. 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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21. Multiple productive immunoglobulin heavy chain gene rearrangements in chronic lymphocytic leukemia are mostly derived from independent clones.

Author

Plevova K, Francova HS, Burckova K, Brychtova Y, Doubek M, Pavlova S, Malcikova J, Mayer J, Tichy B, and Pospisilova S

Subjects
Disease-Free Survival, Female, Humans, Male, Survival Rate, B-Lymphocytes, Gene Rearrangement, B-Lymphocyte, Heavy Chain, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Mutation, Somatic Hypermutation, Immunoglobulin, Tumor Suppressor Protein p53 genetics
Abstract

In chronic lymphocytic leukemia, usually a monoclonal disease, multiple productive immunoglobulin heavy chain gene rearrangements are identified sporadically. Prognostication of such cases based on immunoglobulin heavy variable gene mutational status can be problematic, especially if the different rearrangements have discordant mutational status. To gain insight into the possible biological mechanisms underlying the origin of the multiple rearrangements, we performed a comprehensive immunogenetic and immunophenotypic characterization of 31 cases with the multiple rearrangements identified in a cohort of 1147 patients with chronic lymphocytic leukemia. For the majority of cases (25/31), we provide evidence of the co-existence of at least two B lymphocyte clones with a chronic lymphocytic leukemia phenotype. We also identified clonal drifts in serial samples, likely driven by selection forces. More specifically, higher immunoglobulin variable gene identity to germline and longer complementarity determining region 3 were preferred in persistent or newly appearing clones, a phenomenon more pronounced in patients with stereotyped B-cell receptors. Finally, we report that other factors, such as TP53 gene defects and therapy administration, influence clonal selection. Our findings are relevant to clonal evolution in the context of antigen stimulation and transition of monoclonal B-cell lymphocytosis to chronic lymphocytic leukemia.

Published
2014
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