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

Author

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

Subjects
CLL, clonal evolution, rare subpopulation, refractoriness, single‐cell RNA sequencing, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Early identification of resistant cancer cells is currently a major challenge, as their expansion leads to refractoriness. To capture the dynamics of these cells, we made a comprehensive analysis of disease progression and treatment response in a chronic lymphocytic leukemia (CLL) patient using a combination of single‐cell and bulk genomic methods. At diagnosis, the patient presented with unfavorable genetic markers, including notch receptor 1 (NOTCH1) mutation and loss(11q). The initial and subsequent treatment lines did not lead to a durable response and the patient developed refractory disease. Refractory CLL cells featured substantial dysregulation in B‐cell phenotypic markers such as human leukocyte antigen (HLA) genes, immunoglobulin (IG) genes, CD19 molecule (CD19), membrane spanning 4‐domains A1 (MS4A1; previously known as CD20), CD79a molecule (CD79A) and paired box 5 (PAX5), indicating B‐cell de‐differentiation and disease transformation. We described the clonal evolution and characterized in detail two cell populations that emerged during the refractory disease phase, differing in the presence of high genomic complexity. In addition, we successfully tracked the cells with high genomic complexity back to the time before treatment, where they formed a rare subpopulation. We have confirmed that single‐cell RNA sequencing enables the characterization of refractory cells and the monitoring of their development over time.

Published
2024
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2. Therapeutic strategies and treatment sequencing in patients with chronic lymphocytic leukemia: An international study of ERIC, the European Research Initiative on CLL

Author

Thomas Chatzikonstantinou, Lydia Scarfò, Eva Minga, Georgios Karakatsoulis, Dimitra Chamou, Jana Kotaskova, Gloria Iacoboni, Christos Demosthenous, Elisa Albi, Miguel Alcoceba, Salem Al‐Shemari, Thérèse Aurran‐Schleinitz, Francesca Bacchiarri, Sofia Chatzileontiadou, Rosa Collado, Zadie Davis, Marcos Daniel deDeus Santos, Maria Dimou, Elena Dmitrieva, David Donaldson, Gimena Dos Santos, Barbara Dreta, Maria Efstathopoulou, Shaimaa El‐Ashwah, Alicia Enrico, Andrzej Frygier, Sara Galimberti, Andrea Galitzia, Eva Gimeno, Valerio Guarente, Romain Guieze, Sean Harrop, Eleftheria Hatzimichael, Yair Herishanu, José‐Ángel Hernández‐Rivas, Ozren Jaksic, Elżbieta Kalicińska, Kamel Laribi, Volkan Karakus, Arnon P. Kater, Bonnie Kho, Maria Kislova, Εliana Konstantinou, Maya Koren‐Michowitz, Ioannis Kotsianidis, Zuzana Kubova, Jorge Labrador, Deepesh Lad, Luca Laurenti, Thomas Longval, Alberto Lopez‐Garcia, Juan Marquet, Stanislava Maslejova, Carlota Mayor‐Bastida, Biljana Mihaljevic, Ivana Milosevic, Fatima Miras, Riccardo Moia, Marta Morawska, Uttam K. Nath, Almudena Navarro‐Bailón, Jacopo Olivieri, Irina Panovska‐Stavridis, Maria Papaioannou, Cheyenne Pierie, Anna Puiggros, Gianluigi Reda, Gian M. Rigolin, Rosa Ruchlemer, Mattia Schipani, Annett Schiwitza, Yandong Shen, Tereza Shokralla, Martin Simkovic, Svetlana Smirnova, Dina S. A. Soliman, Stephan Stilgenbauer, Tamar Tadmor, Kristina Tomic, Eric Tse, Theodoros Vassilakopoulos, Andrea Visentin, Candida Vitale, George Vrachiolias, Vojin Vukovic, Renata Walewska, Zhenshu Xu, Munci Yagci, Lucrecia Yañez, Mohamed Yassin, Jana Zuchnicka, David Oscier, Alessandro Gozzetti, Panagiotis Panagiotidis, Francesc Bosch, Paolo Sportoletti, Blanca Espinet, Gerassimos A. Pangalis, Viola M. Popov, Stephen Mulligan, Maria Angelopoulou, Fatih Demirkan, Tomas Papajík, Bella Biderman, Roberta Murru, Marta Coscia, Constantine Tam, Antonio Cuneo, Gianluca Gaidano, Rainer Claus, Niki Stavroyianni, Livio Trentin, Darko Antic, Lukas Smolej, Olga B. Kalashnikova, Mark Catherwood, Martin Spacek, Sarka Pospisilova, Michael Doubek, Eugene Nikitin, Anastasia Chatzidimitriou, Paolo Ghia, and Kostas Stamatopoulos

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2024
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3. Other malignancies in the history of CLL: an international multicenter study conducted by ERIC, the European Research Initiative on CLL, in HARMONYResearch in context

Author

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

Subjects
Chronic lymphocytic leukemia, Other malignancies, Other cancers, Second primary malignancies, Medicine (General), R5-920
Abstract

Summary: Background: Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk factors and CLL-directed treatment is still unclear and represents the focus of this work. Methods: We conducted a retrospective international multicenter study to assess the incidence of OMs and detect potential risk factors in 19,705 patients with CLL, small lymphocytic lymphoma, or high-count CLL-like monoclonal B-cell lymphocytosis, diagnosed between 2000 and 2016. Data collection took place between October 2020 and March 2022. Findings: In 129,254 years of follow-up after CLL diagnosis, 3513 OMs were diagnosed (27.2 OMs/1000 person-years). The most common hematological OMs were Richter transformation, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Non-melanoma skin (NMSC) and prostate cancers were the most common solid tumors (STs).The only predictor for MDS and AML development was treatment with fludarabine and cyclophosphamide with/without rituximab (FC ± R) (OR = 3.7; 95% CI = 2.79–4.91; p

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

Author

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

Subjects
wnt5a, chronic lymphocytic leukaemia, methylation, i-cll, m-cll, Genetics, QH426-470
Abstract

Genome methylation profiles define naïve-like (n-CLL), memory-like (m-CLL), and intermediate (i-CLL) subsets of chronic lymphocytic leukaemia (CLL). The profiles can be easily determined by the analysis of the five-CpG signature. m-CLL, i-CLL, and n-CLL with the good, intermediate, and poor prognoses, respectively, differ by the somatic hypermutation status of the immunoglobulin heavy chain variable gene (IGHV), a widely used prognostic predictor in CLL. We have previously shown that the expression of WNT5A, encoding a ROR1 ligand, distinguishes patients with the worse outcome within the prognostically favourable IGHV-mutated subgroup. To analyse the mechanisms controlling WNT5A expression, we investigated the methylation status of 54 CpG sites within the WNT5A promoter and its relation to the WNT5A gene expression. In a cohort of 59 CLL patients balanced for combinations of IGHV and WNT5A statuses, we identified three promoter CpG sites whose methylation level correlated with the WNT5A expression within the IGHV-mutated subgroup. Further, we complemented our data with the methylation status of the five-CpG signature. IGHV-mutated/WNT5A-negative and IGHV-mutated/WNT5A-positive cases overlapped with m‑CLL and i‑CLL methylation subgroups, respectively, while most IGHV‑unmutated samples were assigned to n-CLL. Median methylation levels of all the three CpG sites in the WNT5A promoter were lowest in i-CLL. Finally, a detailed analysis of m-CLL and i-CLL showed that undetectable WNT5A expression predicts longer treatment-free survival with higher statistical significance than the classification according to the five-CpG signature. To conclude, a favourable m-CLL subgroup is associated with mutated IGHV and undetectable WNT5A expression due to its promoter methylation.

Published
2022
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5. S149: OTHER MALIGNANCIES IN THE HISTORY OF CLL: THE FINAL ANALYSIS OF THE INTERNATIONAL MULTICENTER STUDY CONDUCTED BY ERIC, IN HARMONY.

Author

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

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2023
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6. 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

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

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2023
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7. Evolution of TP53 abnormalities during CLL disease course is associated with telomere length changes

Author

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

Subjects
Chronic Lymphocytic Leukemia, Telomere, TP53, Clonal evolution, BCR signaling, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Telomeres are protective structures at chromosome ends which shorten gradually with increasing age. In chronic lymphocytic leukemia (CLL), short telomeres have been associated with unfavorable disease outcome, but the link between clonal evolution and telomere shortening remains unresolved. Methods We investigated relative telomere length (RTL) in a well-characterized cohort of 198 CLL patients by qPCR and focused in detail on a subgroup 26 patients who underwent clonal evolution of TP53 mutations (evolTP53). In the evolTP53 subgroup we explored factors influencing clonal evolution and corresponding changes in telomere length through measurements of telomerase expression, lymphocyte doubling time, and BCR signaling activity. Results At baseline, RTL of the evolTP53 patients was scattered across the entire RTL spectrum observed in our CLL cohort. RTL changed in the follow-up samples of 16/26 (62%) evolTP53 cases, inclining to reach intermediate RTL values, i.e., longer telomeres shortened compared to baseline while shorter ones prolonged. For the first time we show that TP53 clonal shifts are linked to RTL change, including unexpected RTL prolongation. We further investigated parameters associated with RTL changes. Unstable telomeres were significantly more frequent among younger patients (P = 0.032). Shorter telomeres were associated with decreased activity of the B-cell receptor signaling components p-ERK1/2, p-ZAP-70/SYK, and p-NFκB (P = 0.04, P = 0.01, and P = 0.02, respectively). Conclusions Our study revealed that changes of telomere length reflect evolution in leukemic subclone proportion, and are associated with specific clinico-biological features of the explored cohort.

Published
2022
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8. Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia

Author

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

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Chronic lymphocytic leukemia (CLL) patients with differential somatic hypermutation status of the immunoglobulin heavy variable genes, namely mutated or unmutated, display fundamental clinico-biological differences. Considering this, we assessed prognosis separately within mutated (M-CLL) and unmutated (U-CLL) CLL in 3015 patients, hypothesizing that the relative significance of relevant indicators may differ between these two categories. Within Binet A M-CLL patients, besides TP53 abnormalities, trisomy 12 and stereotyped subset #2 membership were equivalently associated with the shortest time-to-first-treatment and a treatment probability at five and ten years after diagnosis of 40% and 55%, respectively; the remaining cases exhibited 5-year and 10-year treatment probability of 12% and 25%, respectively. Within Binet A U-CLL patients, besides TP53 abnormalities, del(11q) and/or SF3B1 mutations were associated with the shortest time-to-first-treatment (5- and 10-year treatment probability: 78% and 98%, respectively); in the remaining cases, males had a significantly worse prognosis than females. In conclusion, the relative weight of indicators that can accurately risk stratify early-stage CLL patients differs depending on the somatic hypermutation status of the immunoglobulin heavy variable genes of each patient. This finding highlights the fact that compartmentalized approaches based on immunogenetic features are necessary to refine and tailor prognostication in CLL.

Published
2019
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9. 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

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

Subjects
Cancer Research, Oncology, Genetics research, Hematology, Cancer genetics
Published
2023

10. LYmphoid NeXt-Generation Sequencing (LYNX) Panel: A Comprehensive Capture-Based Sequencing Tool for the Analysis of Prognostic and Predictive Markers in Lymphoid Malignancies

Author

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

Subjects
Chromosome Aberrations, DNA Copy Number Variations, Lymphoma, Computational Biology, Genetic Variation, High-Throughput Nucleotide Sequencing, Genomics, Prognosis, Translocation, Genetic, Leukemia, Lymphoid, INDEL Mutation, Molecular Diagnostic Techniques, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease
Abstract

B-cell neoplasms represent a clinically heterogeneous group of hematologic malignancies with considerably diverse genomic architecture recently endorsed by next-generation sequencing (NGS) studies. Because multiple genetic defects have a potential or confirmed clinical impact, a tendency toward more comprehensive testing of diagnostic, prognostic, and predictive markers is desired. This study introduces the design, validation, and implementation of an integrative, custom-designed, capture-based NGS panel titled LYmphoid NeXt-generation sequencing (LYNX) for the analysis of standard and novel molecular markers in the most common lymphoid neoplasms (chronic lymphocytic leukemia, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma). A single LYNX test provides the following: i) accurate detection of mutations in all coding exons and splice sites of 70 lymphoma-related genes with a sensitivity of 5% variant allele frequency, ii) reliable identification of large genome-wide (≥6 Mb) and recurrent chromosomal aberrations (≥300 kb) in at least 20% of the clonal cell fraction, iii) the assessment of immunoglobulin and T-cell receptor gene rearrangements, and iv) lymphoma-specific translocation detection. Dedicated bioinformatic pipelines were designed to detect all markers mentioned above. The LYNX panel represents a comprehensive, up-to-date tool suitable for routine testing of lymphoid neoplasms with research and clinical applicability. It allows a wide adoption of capture-based targeted NGS in clinical practice and personalized management of patients with lymphoproliferative diseases.

Published
2020

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

Author

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

Subjects
Oncology, medicine.medical_specialty, Proportional hazards model, business.industry, Chronic lymphocytic leukemia, Immunology, Somatic hypermutation, Recursive partitioning, Cell Biology, Hematology, medicine.disease, Biochemistry, Log-rank test, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Internal medicine, Cohort, medicine, Clinical endpoint, IGHV@, business, 030215 immunology
Abstract

The classification of CLL patients according to the somatic hypermutation status (SHM) of the immunoglobulin heavy variable (IGHV) genes, namely mutated (M-CLL) versus unmutated (U-CLL), reflects fundamental differences in disease biology and clinical course. Realizing this, here we followed a compartmentalized approach and addressed the issue of prognostication separately for M-CLL and U-CLL. In a multi-institutional cohort of 2366 patients [M-CLL, n=1364 (58%); U-CLL, n=1002 (42%)] consolidated within ERIC, the European Initiative in CLL, we assessed the clinical impact of 'traditional' (age and clinical stage at the time of diagnosis, gender, CD38 expression, FISH detected abnormalities included in the Döhner hierarchical model of cytogenetic aberrations), and novel prognosticators (recurrent mutations within the TP53, SF3B1, NOTCH1, MYD88, and BIRC3 genes; IGHV gene usage; membership in stereotyped subsets) within M-CLL and U-CLL. Our statistical approach was based both on Cox regression models and recursive partitioning algorithms; internal validation was performed via bootstrapping procedures. Given the retrospective nature of our study, time-to-first-treatment (TTFT) was the primary endpoint. As expected, M-CLL exhibited significantly longer TTFT compared to U-CLL [median TTFT: not yet reached (M-CLL) vs 1.9 years (95% CI: 0.01-12.3 years, U-CLL), p PB and TM contributed equally as first authors Figure 1 Figure 1. Disclosures Rosenquist: Gilead Sciences: Speakers Bureau.

Published
2016
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13. Lyn Phosphorylates and Controls ROR1 Surface Dynamics During Chemotaxis of CLL Cells

Author

Zankruti Dave, Olga Vondálová Blanářová, Štěpán Čada, Pavlína Janovská, Nikodém Zezula, Martin Běhal, Kateřina Hanáková, Sri Ranjani Ganji, Pavel Krejci, Kristína Gömöryová, Helena Peschelová, Michal Šmída, Zbyněk Zdráhal, Šárka Pavlová, Jana Kotašková, Šárka Pospíšilová, and Vítězslav Bryja

Subjects
Ror1, Lyn, crosstalk, phosphorylation, CLL, BCR, Biology (General), QH301-705.5
Abstract

Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are malignancies characterized by the dependence on B-cell receptor (BCR) signaling and by the high expression of ROR1, the cell surface receptor for Wnt-5a. Both, BCR and ROR1 are therapeutic targets in these diseases and the understanding of their mutual cross talk is thus of direct therapeutic relevance. In this study we analyzed the role of Lyn, a kinase from the Src family participating in BCR signaling, as a mediator of the BCR-ROR1 crosstalk. We confirm the functional interaction between Lyn and ROR1 and demonstrate that Lyn kinase efficiently phosphorylates ROR1 in its kinase domain and aids the recruitment of the E3 ligase c-CBL. We show that ROR1 surface dynamics in migrating primary CLL cells as well as chemotactic properties of CLL cells were inhibited by Lyn inhibitor dasatinib. Our data establish Lyn-mediated phosphorylation of ROR1 as a point of crosstalk between BCR and ROR1 signaling pathways.

Published
2022
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14. Additional trisomies amongst patients with chronic lymphocytic leukemia carrying trisomy 12: the accompanying chromosome makes a difference

Author

Panagiotis Baliakas, Anna Puiggros, Aliki Xochelli, Lesley-Ann Sutton, Florence Nguyen-Khac, Anne Gardiner, Karla Plevova, Eva Minga, Anastasia Hadzidimitriou, Renata Walewska, Helen McCarthy, Margarita Ortega, Rosa Collado, Teresa González, Isabel Granada, Elisa Luño, Jana Kotašková, Theodoros Moysiadis, Zadie Davis, Niki Stavroyianni, Achilles Anagnostopoulos, Jonathan C. Strefford, Sarka Pospisilova, Frederic Davi, Anastasia Athanasiadou, Richard Rosenquist, David Oscier, Blanca Espinet, and Kostas Stamatopoulos

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2016
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