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1. BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib

Author

Bonfiglio, Silvia, Sutton, Lesley-Ann, Ljungström, Viktor, Capasso, Antonella, Pandzic, Tatjana, Weström, Simone, Foroughi-Asl, Hassan, Skaftason, Aron, Gellerbring, Anna, Lyander, Anna, Gandini, Francesca, Gaidano, Gianluca, Trentin, Livio, Bonello, Lisa, Reda, Gianluigi, Bödör, Csaba, Stavroyianni, Niki, Tam, Constantine S., Marasca, Roberto, Forconi, Francesco, Panayiotidis, Panayiotis, Ringshausen, Ingo, Jaksic, Ozren, Frustaci, Anna Maria, Iyengar, Sunil, Coscia, Marta, Mulligan, Stephen P., Ysebaert, Loïc, Strugov, Vladimir, Pavlovsky, Carolina, Walewska, Renata, Österborg, Anders, Cortese, Diego, Ranghetti, Pamela, Baliakas, Panagiotis, Stamatopoulos, Kostas, Scarfò, Lydia, Rosenquist, Richard, and Ghia, Paolo

Published
2023
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2. Frequent mutations of FBXO11 highlight BCL6 as a therapeutic target in Burkitt lymphoma

Author

Pighi, Chiara, Cheong, Taek-Chin, Compagno, Mara, Patrucco, Enrico, Arigoni, Maddalena, Olivero, Martina, Wang, Qi, López, Cristina, Bernhart, Stephan H., Grande, Bruno M., Poggio, Teresa, Langellotto, Fernanda, Bonello, Lisa, Dall'Olio, Riccardo, Martínez-Martín, Sandra, Molinaro, Luca, Francia di Celle, Paola, Whitfield, Jonathan R., Soucek, Laura, Voena, Claudia, Calogero, Raffaele A., Morin, Ryan D., Staudt, Louis M., Siebert, Reiner, Zamò, Alberto, and Chiarle, Roberto

Published
2021
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3. 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, Scarfò, Lydia, van Gastel, Ellen J., Armand, Marine, Tausch, Eugen, Biderman, Bella, Baer, Constance, Bagnara, Davide, Navarro, Alba, Langlois de Septenville, Anne, 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, Skuhrova Francova, Hana, Moysiadis, Theodoros, Veronese, Silvio, Giannopoulos, Krzysztof, Mansouri, Larry, Karan-Djurasevic, Teodora, Sandaltzopoulos, Raphael, Bödör, 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, Francia di Celle, Paola, 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

Published
2021
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4. In pancreatic cancer patients, chemotherapy reshapes the gene expression profile and antigen receptor repertoire of T lymphocytes and enhances their effector response to tumor-associated antigens.

Author

Brugiapaglia, Silvia, Bulfamante, Sara, Curcio, Claudia, Arigoni, Maddalena, Calogero, Raffaele, Bonello, Lisa, Genuardi, Elisa, Spadi, Rosella, Satolli, Maria Antonietta, Campra, Donata, Giordano, Daniele, Cappello, Paola, Cordero, Francesca, and Novelli, Francesco

Subjects
REGULATORY T cells, T cell receptors, T cells, GENE expression profiling, PANCREATIC duct
Abstract

Introduction: Pancreatic Ductal Adenocarcinoma (PDA) is one of the most aggressive malignancies with a 5-year survival rate of 13%. Less than 20% of patients have a resectable tumor at diagnosis due to the lack of distinctive symptoms and reliable biomarkers. PDA is resistant to chemotherapy (CT) and understanding how to gain an anti-tumor effector response following stimulation is, therefore, critical for setting up an effective immunotherapy. Methods: Proliferation, and cytokine release and TCRB repertoire of from PDA patient peripheral T lymphocytes, before and after CT, were analyzed in vitro in response to four tumor-associated antigens (TAA), namely ENO1, FUBP1, GAPDH and K2C8. Transcriptional state of PDA patient PBMC was investigated using RNA-Seq before and after CT. Results: CT increased the number of TAA recognized by T lymphocytes, which positively correlated with patient survival, and high IFN-g production TAAinduced responses were significantly increased after CT. We found that some ENO1-stimulated T cell clonotypes from CT-treated patients were expanded or de-novo induced, and that some clonotypes were reduced or even disappeared after CT. Patients that showed a higher number of effector responses to TAA (high IFN-g/IL-10 ratio) after CT expressed increased fatty acid-related transcriptional signature. Conversely, patients that showed a higher number of regulatory responses to TAA (low IFN-g/IL-10 ratio) after CT significantly expressed an increased IRAK1/IL1R axis-related transcriptional signature. Conclusion: These data suggest that the expression of fatty acid or IRAK1/IL1Rrelated genes predicts T lymphocyte effector or regulatory responses to TAA in patients that undergo CT. These findings are a springboard to set up precision immunotherapies in PDA based on the TAA vaccination in combination with CT. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Case Report: Sequential Development of Three Mature Lymphoid Neoplasms in a Single Patient: Clonal Relationship and Molecular Insights

Author

Salvetti, Chiara, Vitale, Candida, Griggio, Valentina, Drandi, Daniela, Jones, Rebecca, Bonello, Lisa, Bomben, Riccardo, Bragoni, Alberto, Bagnara, Davide, Fais, Franco, Gattei, Valter, Cavallo, Federica, Zamò, Alberto, and Coscia, Marta

Subjects
Hodgkin lymphoma, IGHV genes, Richter’s syndrome, chronic lymphocytic leukemia, monoclonal B-cell lymphocytosis, Cancer Research, Oncology
Abstract

Two main variants of Richter syndrome (RS) are recognized, namely, the diffuse large B-cell lymphoma (DLBCL) and the Hodgkin’s lymphoma (HL) variant. Clonal relationship, defined as an identity of the immunoglobulin heavy chain variable (IGHV) region sequence between chronic lymphocytic leukemia (CLL) and RS clones, characterizes patients with a poor prognosis. Due to method sensitivity, this categorization is performed without considering the possibility of small-size ancillary clones, sharing the same phenotype with the preexisting predominant CLL clone, but with different IGHV rearrangements. Here we describe and molecularly profile the peculiar case of a patient with a CLL-like monoclonal B-cell lymphocytosis (MBL), who sequentially developed a DLBCL, which occurred concomitantly to progression of MBL to CLL, and a subsequent HL. Based on standard IGHV clonality analysis, DLBCL was considered clonally unrelated to the concomitantly expanded CLL clone and treated as a de novo lymphoma, achieving a persistent response. Three years later, the patient further developed a clonally unrelated HL, refractory to bendamustine, which was successfully treated with brentuximab vedotin and radiotherapy, and later with pembrolizumab. We retrospectively performed additional molecular testing, by applying next-generation sequencing (NGS) of immunoglobulin repertoire (Ig-rep) techniques and a more sensitive allele-specific oligonucleotide-droplet digital PCR (ASO-ddPCR) strategy, in order to quantitatively investigate the presence of the rearranged IGHV genes in tumor specimens collected during the disease course. In this highly complex case, the application of modern and sensitive molecular technologies uncovered that DLBCL, initially considered as a de novo lymphoma, was instead the result of the transformation of a preexisting ancillary B-cell clone, which was already present at the time of first MBL diagnosis. A similar approach was also applied on the HL sample, showing its clonal unrelatedness to the previous MBL and DLBCL.

Published
2022
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7. Immunoglobulin heavy variable (IGHV) genes and alleles: new entities, new names and implications for research and prognostication in chronic lymphocytic leukaemia

Author

Xochelli, Aliki, Agathangelidis, Andreas, Kavakiotis, Ioannis, Minga, Evangelia, Sutton, Lesley Ann, Baliakas, Panagiotis, Chouvarda, Ioanna, Giudicelli, Véronique, Vlahavas, Ioannis, Maglaveras, Nikos, Bonello, Lisa, Trentin, Livio, Tedeschi, Alessandra, Panagiotidis, Panagiotis, Geisler, Christian, Langerak, Anton W., Pospisilova, Sarka, Jelinek, Diane F., Oscier, David, Chiorazzi, Nicholas, Darzentas, Nikos, Davi, Fred, Ghia, Paolo, Rosenquist, Richard, Hadzidimitriou, Anastasia, Belessi, Chrysoula, Lefranc, Marie-Paule, and Stamatopoulos, Kostas

Published
2015
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8. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies

Author

Agathangelidis, Andreas, Darzentas, Nikos, Hadzidimitriou, Anastasia, Brochet, Xavier, Murray, Fiona, Yan, Xiao-Jie, Davis, Zadie, van Gastel-Mol, Ellen J., Tresoldi, Cristina, Chu, Charles C., Cahill, Nicola, Giudicelli, Veronique, Tichy, Boris, Pedersen, Lone Bredo, Foroni, Letizia, Bonello, Lisa, Janus, Agnieszka, Smedby, Karin, Anagnostopoulos, Achilles, Merle-Beral, Helene, Laoutaris, Nikolaos, Juliusson, Gunnar, di Celle, Paola Francia, Pospisilova, Sarka, Jurlander, Jesper, Geisler, Christian, Tsaftaris, Athanasios, Lefranc, Marie-Paule, Langerak, Anton W., Oscier, David Graham, Chiorazzi, Nicholas, Belessi, Chrysoula, Davi, Frederic, Rosenquist, Richard, Ghia, Paolo, and Stamatopoulos, Kostas

Published
2012
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14. Specific Detection of Cytokeratin 20-Positive Cells in Blood of Colorectal and Breast Cancer Patients by a High Sensitivity Real-Time Reverse Transcriptase-Polymerase Chain Reaction Method

Author

Giribaldi, Giuliana, Procida, Simone, Ulliers, Daniela, Mannu, Franca, Volpatto, Roberta, Mandili, Giorgia, Fanchini, Laura, Bertetto, Oscar, Fronda, Gianruggero, Simula, Luigi, Rimini, Elena, Cherchi, Giovanni, Bonello, Lisa, Maule, Milena Maria, and Turrini, Francesco

Published
2006
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17. HIF-1α is over-expressed in leukemic cells from TP53-disrupted patients and is a promising therapeutic target in chronic lymphocytic leukemia

Author

Griggio, Valentina, primary, Vitale, Candida, additional, Todaro, Maria, additional, Riganti, Chiara, additional, Kopecka, Joanna, additional, Salvetti, Chiara, additional, Bomben, Riccardo, additional, Bo, Michele Dal, additional, Magliulo, Daniela, additional, Rossi, Davide, additional, Pozzato, Gabriele, additional, Bonello, Lisa, additional, Marchetti, Monia, additional, Omedè, Paola, additional, Kodipad, Ahad Ahmed, additional, Laurenti, Luca, additional, Del Poeta, Giovanni, additional, Mauro, Francesca Romana, additional, Bernardi, Rosa, additional, Zenz, Thorsten, additional, Gattei, Valter, additional, Gaidano, Gianluca, additional, Foà, Robin, additional, Massaia, Massimo, additional, Boccadoro, Mario, additional, and Coscia, Marta, additional

Published
2019
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18. Regulation of HIF-1 α in TP53 Disrupted Chronic Lymphocytic Leukemia Cells and Its Potential Role as a Therapeutic Target

Author

Vitale, Candida, primary, Griggio, Valentina, additional, Todaro, Maria, additional, Riganti, Chiara, additional, Kopecka, Joanna, additional, Salvetti, Chiara, additional, Bomben, Riccardo, additional, Bo, Michele Dal, additional, Rossi, Davide, additional, Pozzato, Gabriele, additional, Marchetti, Monia, additional, Omedè, Paola, additional, Bonello, Lisa, additional, Kodipad, Ahad Ahmed, additional, Laurenti, Luca, additional, Del Poeta, Giovanni, additional, Mauro, Francesca Romana, additional, Bernardi, Rosa, additional, Gattei, Valter, additional, Gaidano, Gianluca, additional, Foà, Robin, additional, Massaia, Massimo, additional, Boccadoro, Mario, additional, and Coscia, Marta, additional

Published
2018
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19. TCRγ-Chain Gene Rearrangement by PCR-Based GeneScan: Diagnostic Accuracy Improvement and Clonal Heterogeneity Analysis in Multiple Cutaneous T-Cell Lymphoma Samples

Author

Francia di Celle Paola, Ortoncelli Michela, Renata Ponti, Mauro Novelli, Bonello Lisa, Fava Paolo, Maria Teresa Fierro, Maria Grazia Bernengo, Pietro Quaglino, and Alessandra Comessatti

Subjects
Male, Pathology, medicine.medical_specialty, Skin Neoplasms, Biopsy, T-Lymphocytes, Population, clonality, Dermatology, Biology, Polymerase Chain Reaction, Biochemistry, law.invention, Diagnosis, Differential, Mycosis Fungoides, CTCL, law, medicine, Humans, Sezary Syndrome, Multiplex, education, Molecular Biology, Polymerase chain reaction, Skin, Mycosis fungoides, education.field_of_study, Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor, Cutaneous T-cell lymphoma, Electrophoresis, Capillary, heteroduplex PCR, Cell Biology, Gene rearrangement, medicine.disease, Molecular biology, Clone Cells, Lymphoma, T-Cell, Cutaneous, Chain gene, Female, Heteroduplex
Abstract

Cutaneous T-cell lymphomas are a heterogeneous group of lymphomas where the tumor population emerges within a multiple subclone pattern ("clonal heterogeneity"). PCR analysis has been shown to be useful in the diagnosis of mycosis fungoides (MF) and Sézary Syndrome (SS). Focusing the attention on clonal heterogeneity, the efficacy of the multiplex/heteroduplex (HD) PCR and the GeneScan (GS) capillary electrophoresis analysis was compared in the early diagnosis of MF/SS, using a multiple sample approach. Indeed, GS demonstrated TCRgamma gene rearrangement (GR) in all the 57 SS (100%) and in 123/146 (84%) of the MF samples, whereas the multiplex/HD PCR was less sensitive. An increase in clonality was observed in connection with both a worsening of the cutaneous disease (79% T1/T2; 100% T3/T4) and an increase in the histopathological score (HS5, 76%; HSor = 5, 94%). Clonal heterogeneity with adjunctive reproducible skin TCRgamma-GRs was also observed. "Clonal instability," with different GRs, was present in a small percentage of patients. Therefore, it can be concluded that GS analysis in TCRgamma-GR is able to improve diagnosis in MF/SS patients and the multiple sample approach is helpful for a correct interpretation of clonal patterns in skin lesions, especially in early-stage MF and in SS skin/blood samples.

Published
2008
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21. Immunoglobulin Heavy Chain Variable Genes and Alleles: New Entities, New Names and Implications for Research and Prognostication in CLL

Author

Xochelli, A, Agathangelidis, A, Kavakiotis, I, Minga, E, Sutton, La, Baliakas, P, Chouvarda, I, Giudicelli, V, Vlahavas, I, Maglaveras, N, Bonello, Lisa, Trentin, L, Montillo, M, Panagiotidis, P, Geisler, C, Langerak, Aw, Pospisilova, S, Jelinek, Df, Oscier, D, Chiorazzi, N, Darzentas, N, Davi, F, Ghia, P, Rosenquist, R, Hadzidimitriou, A, Belessi, C, Lefranc, Mp, and Stamatopoulos, K.

Published
2014

22. Peripheral ENO1-specific T cells mirror the intratumoral immune response and their presence is a potential prognostic factor for pancreatic adenocarcinoma

Author

NICCOLAI, ELENA, primary, CAPPELLO, PAOLA, additional, TADDEI, ANTONIO, additional, RICCI, FEDERICA, additional, D'ELIOS, MARIO MILCO, additional, BENAGIANO, MARISA, additional, BECHI, PAOLO, additional, BENCINI, LAPO, additional, RINGRESSI, MARIA NOVELLA, additional, CORATTI, ANDREA, additional, CIANCHI, FABIO, additional, BONELLO, LISA, additional, DI CELLE, PAOLA FRANCIA, additional, PRISCO, DOMENICO, additional, NOVELLI, FRANCESCO, additional, and AMEDEI, AMEDEO, additional

Published
2016
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23. Usefulness of multiparametric flow cytometry in detecting composite lymphoma: study of 17 cases in a 12-year period

Author

Demurtas, Anna, Aliberti, Sabrina, Bonello, Lisa, Di Celle, Paola Francia, Cavaliere, Cristina, Barreca, Antonella, Novero, Domenico, and Stacchini, Alessandra

Subjects
Aged, 80 and over, Male, Lymphoma, B-Cell, Lymphoma, Lymphoma, Non-Hodgkin, B-Cell, Non-Hodgkin, Middle Aged, Biological, Flow Cytometry, Hodgkin Disease, Tissue biopsy, Immunophenotyping, Composite Lymphoma, Composite lymphoma, Flow cytometry, Aged, Female, Humans, Retrospective Studies, Tumor Markers, Biological, 2734, 80 and over, Biomarkers, Tumor, Tumor Markers
Abstract

Composite lymphoma (CL) is a rare occurrence of 2 or more morphologically and immunophenotypically distinct lymphoma clones in a single anatomic site. A retrospective analysis of 1,722 solid tissue samples clinically suggestive of lymphoma was carried out in our institute during a 12-year period to evaluate the efficacy of flow cytometry (FC) in identifying CL. We report 17 CL cases. A strong correlation between morphologic findings and FC was observed in 13 cases (76%). In the 4 cases diagnosed as non-Hodgkin lymphoma plus Hodgkin lymphoma, although FC did not detect Reed-Sternberg cells, it accurately identified the neoplastic B- or T-cell component. In 3 cases, FC indicated the need to evaluate an additional neoplastic component that was not morphologically evident. Our data demonstrate that FC immunophenotyping of tissues may enhance the performance of the diagnostic morphologic evaluation of CL. To the best of our knowledge, this is the first report in the literature of a wide series of CL studied also by FC.

Published
2011

25. Flexible Lab-Tailored Cut-Offs for Suitability of Formalin-Fixed Tumor Samples for Diagnostic Mutational Analyses

Author

Mariani, Sara, primary, Di Bello, Cristiana, additional, Bonello, Lisa, additional, Tondat, Fabrizio, additional, Pacchioni, Donatella, additional, Molinaro, Luca, additional, Barreca, Antonella, additional, Macrì, Luigia, additional, Chiusa, Luigi, additional, di Celle, Paola Francia, additional, Cassoni, Paola, additional, and Sapino, Anna, additional

Published
2015
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27. Immunoglobulin heavy variable (IGHV) genes and alleles: new entities, new names and implications for research and prognostication in chronic lymphocytic leukaemia

Author

Xochelli, Aliki, primary, Agathangelidis, Andreas, additional, Kavakiotis, Ioannis, additional, Minga, Evangelia, additional, Sutton, Lesley Ann, additional, Baliakas, Panagiotis, additional, Chouvarda, Ioanna, additional, Giudicelli, Véronique, additional, Vlahavas, Ioannis, additional, Maglaveras, Nikos, additional, Bonello, Lisa, additional, Trentin, Livio, additional, Tedeschi, Alessandra, additional, Panagiotidis, Panagiotis, additional, Geisler, Christian, additional, Langerak, Anton W., additional, Pospisilova, Sarka, additional, Jelinek, Diane F., additional, Oscier, David, additional, Chiorazzi, Nicholas, additional, Darzentas, Nikos, additional, Davi, Fred, additional, Ghia, Paolo, additional, Rosenquist, Richard, additional, Hadzidimitriou, Anastasia, additional, Belessi, Chrysoula, additional, Lefranc, Marie-Paule, additional, and Stamatopoulos, Kostas, additional

Published
2014
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28. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia:a molecular classification with implications for targeted therapies

Author

Agathangelidis, Andreas, Darzentas, Nikos, Hadzidimitriou, Anastasia, Brochet, Xavier, Murray, Fiona, Yan, Xiao-Jie, Davis, Zadie, van Gastel-Mol, Ellen J, Tresoldi, Cristina, Chu, Charles C, Cahill, Nicola, Giudicelli, Veronique, Tichy, Boris, Pedersen, Lone Bredo, Foroni, Letizia, Bonello, Lisa, Janus, Agnieszka, Smedby, Karin, Anagnostopoulos, Achilles, Merle-Beral, Helene, Laoutaris, Nikolaos, Juliusson, Gunnar, di Celle, Paola Francia, Pospisilova, Sarka, Jurlander, Jesper, Geisler, Christian, Tsaftaris, Athanasios, Lefranc, Marie-Paule, Langerak, Anton W, Oscier, David Graham, Chiorazzi, Nicholas, Belessi, Chrysoula, Davi, Frederic, Rosenquist, Richard, Ghia, Paolo, Stamatopoulos, Kostas, Agathangelidis, Andreas, Darzentas, Nikos, Hadzidimitriou, Anastasia, Brochet, Xavier, Murray, Fiona, Yan, Xiao-Jie, Davis, Zadie, van Gastel-Mol, Ellen J, Tresoldi, Cristina, Chu, Charles C, Cahill, Nicola, Giudicelli, Veronique, Tichy, Boris, Pedersen, Lone Bredo, Foroni, Letizia, Bonello, Lisa, Janus, Agnieszka, Smedby, Karin, Anagnostopoulos, Achilles, Merle-Beral, Helene, Laoutaris, Nikolaos, Juliusson, Gunnar, di Celle, Paola Francia, Pospisilova, Sarka, Jurlander, Jesper, Geisler, Christian, Tsaftaris, Athanasios, Lefranc, Marie-Paule, Langerak, Anton W, Oscier, David Graham, Chiorazzi, Nicholas, Belessi, Chrysoula, Davi, Frederic, Rosenquist, Richard, Ghia, Paolo, and Stamatopoulos, Kostas

Abstract

Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotyped BCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency as well as the identification of "CLL-biased" features in BCR Ig stereotypes. To this end, we examined 7596 Ig VH (IGHV-IGHD-IGHJ) sequences from 7424 CLL patients, 3 times the size of the largest published series, with an updated version of our purpose-built clustering algorithm. We document that CLL may be subdivided into 2 distinct categories: one with stereotyped and the other with nonstereotyped BCRs, at an approximate ratio of 1:2, and provide evidence suggesting a different ontogeny for these 2 categories. We also show that subset-defining sequence patterns in CLL differ from those underlying BCR stereotypy in other B-cell malignancies. Notably, 19 major subsets contained from 20 to 213 sequences each, collectively accounting for 943 sequences or one-eighth of the cohort. Hence, this compartmentalized examination of VH sequences may pave the way toward a molecular classification of CLL with implications for targeted therapeutic interventions, applicable to a significant number of patients assigned to the same subset.

Published
2012

30. Description of a novel Janus kinase 3 P132A mutation in acute megakaryoblastic leukemia and demonstration of previously reported Janus kinase 3 mutations in normal subjects

Author

Riera, Ludovica, primary, Lasorsa, Elena, additional, Bonello, Lisa, additional, Sismondi, Francesca, additional, Tondat, Fabrizio, additional, Di Bello, Cristiana, additional, Di Celle, Paola Francia, additional, Chiarle, Roberto, additional, Godio, Laura, additional, Pich, Achille, additional, Facchetti, Fabio, additional, Ponzoni, Maurilio, additional, Marmont, Filippo, additional, Zanon, Carlo, additional, Bardelli, Alberto, additional, and Inghirami, Giorgio, additional

Published
2011
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32. Abstract LB-309: EML4-ALK signaling is required for the maintenance of neoplastic phenotype of non-small cell lung cancer cells: Novel strategy for lung cancer-tailored therapies

Author

Voena, Claudia, primary, Panizza, Elena, additional, D'Amico, Lucia, additional, Ambrogio, Chiara, additional, Cinzia, Martinengo, additional, Boccalatte, Francesco, additional, Riera, Ludovica, additional, Bonello, Lisa, additional, Pulito, Roberta, additional, Hamm, Jorg, additional, Cheng, Mangeng, additional, Ruggeri, Bruce, additional, Gu, Ting-Lei, additional, Polakiewicz, Roberto D., additional, Medico, Enzo, additional, Chiarle, Roberto, additional, and Inghirami, Giorgio, additional

Published
2010
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33. CD38 Induces Homing of Chronic Lymphocytic Leukemia Cells to the Lymphoid Organs through a Functional Interplay with CXCR4.

Author

Deaglio, Silvia, primary, Aydin, Semra, additional, Vaisitti, Tiziana, additional, Bergui, Luciana, additional, Rossi, Davide, additional, D'Arena, Giovanni, additional, Bonello, Lisa, additional, Mello Grand, Maurizia, additional, Chiorino, Giovanna, additional, Horenstein, Alberto, additional, Gaidano, Gianluca, additional, and Malavasi, Fabio, additional

Published
2009
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40. Predicting gefitinib responsiveness in lung cancer by fluorescence in situ hybridization/chromogenic in situ hybridization analysis of EGFR and HER2 in biopsy and cytology specimens

Author

Daniele, Lorenzo, primary, Macrì, Luigia, additional, Schena, Marina, additional, Dongiovanni, Diego, additional, Bonello, Lisa, additional, Armando, Enrico, additional, Ciuffreda, Libero, additional, Bertetto, Oscar, additional, Bussolati, Gianni, additional, and Sapino, Anna, additional

Published
2007
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41. IL-7 Up-Regulates TNF-α-Dependent Osteoclastogenesis in Patients Affected by Solid Tumor

Author

Roato, Ilaria, primary, Brunetti, Giacomina, additional, Gorassini, Eva, additional, Grano, Maria, additional, Colucci, Silvia, additional, Bonello, Lisa, additional, Buffoni, Lucio, additional, Manfredi, Roberto, additional, Ruffini, Enrico, additional, Ottaviani, Davide, additional, Ciuffreda, Libero, additional, Mussa, Antonio, additional, and Ferracini, Riccardo, additional

Published
2006
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42. Follicular Origin of a Subset of CD5+ Diffuse Large B-Cell Lymphomas

Author

Manazza, Andrea D., primary, Bonello, Lisa, additional, Pagano, Marco, additional, Chiusa, Luigi, additional, Novero, Domenico, additional, Stacchini, Alessandra, additional, Martini, Giuseppe, additional, Vitolo, Umberto, additional, Tarella, Corrado, additional, Inghirami, Giorgio, additional, Palestro, Giorgio, additional, and Chiarle, Roberto, additional

Published
2005
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43. Concurrent Rituximab with Dose-Dense MegaCEOP Chemotherapy and High Dose Mitoxantrone, Ara-C and Dexamethasone (MAD) Followed by BEAM and Autologous Stem Cell Transplantation (ASCT) Is Feasible and Effective in High Risk Diffuse Large B-Cell Lymphoma (B-DLCL): A Multicenter Pilot Study.

Author

Vitolo, Umberto, primary, Liberati, Anna Marina, additional, Cabras, Maria Giuseppina, additional, Rossi, Giuseppe, additional, Levis, Alessandro, additional, Pavone, Enzo, additional, Angelucci, Emanuele, additional, Boccomini, Carola, additional, Bonello, Lisa, additional, Botto, Barbara, additional, Chiappella, Annalisa, additional, Di Vito, Francesco, additional, Palumbo, Isabella, additional, Pogliani, Enrico, additional, Rota-Scalabrini, Delia, additional, Salvi, Flavia, additional, Tonso, Anna, additional, Tucci, Alessandra, additional, and Gallo, Eugenio, additional

Published
2004
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44. BTKand PLCG2remain unmutated in one third of patients with CLL relapsing on ibrutinib

Author

Bonfiglio, Silvia, Sutton, Lesley-Ann, Ljungström, Viktor, Capasso, Antonella, Pandzic, Tatjana, Weström, Simone, Foroughi-Asl, Hassan, Skaftason, Aron, Gellerbring, Anna, Lyander, Anna, Gandini, Francesca, Gaidano, Gianluca, Trentin, Livio, Bonello, Lisa, Reda, Gianluigi, Bödör, Csaba, Stavroyianni, Niki, Tam, Constantine S., Marasca, Roberto, Forconi, Francesco, Panayiotidis, Panayiotis, Ringshausen, Ingo, Jaksic, Ozren, Frustaci, Anna Maria, Iyengar, Sunil, Coscia, Marta, Mulligan, Stephen P., Ysebaert, Loïc, Strugov, Vladimir, Pavlovsky, Carolina, Walewska, Renata, Österborg, Anders, Cortese, Diego, Ranghetti, Pamela, Baliakas, Panagiotis, Stamatopoulos, Kostas, Scarfò, Lydia, Rosenquist, Richard, and Ghia, Paolo

Abstract

•One third of patients with CLL relapsing on ibrutinib do not carry BTK/PLCG2mutations, even with a 0.1% sensitivity.•Additional mechanisms, such as del(8p), EGR2and NF-κB pathway mutations, may be cooperating in determining progression on ibrutinib.

Published
2023
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45. Myelodysplastic syndrome with del (5q) and JAK2(V617F) mutation transformed to acute myeloid leukaemia with complex karyotype.

Author

Francia di Celle, Paola, Pich, Achille, Godio, Laura, Riera, Ludovica, Cavaliere, Cristina, Kerim, Simonetta, and Bonello, Lisa

Subjects
MYELODYSPLASTIC syndromes, ACUTE myeloid leukemia, KARYOTYPES, ACUTE myeloid leukemia diagnosis, CHROMOSOMES, GENETIC mutation, PROTEINS, DISEASE complications, MACROCYTIC anemia, DIAGNOSIS
Abstract

A letter to the editor is presented regarding the transformation of Myelodysplastic syndrome with del (5q) and JAK2 mutation to acute myeloid leukaemia with complex karyotype.

Published
2016
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46. CD38gene polymorphism and chronic lymphocytic leukemia: a role in transformation to Richter syndrome?

Author

Aydin, Semra, Rossi, Davide, Bergui, Luciana, D'Arena, Giovanni, Ferrero, Enza, Bonello, Lisa, Omedé, Paola, Novero, Domenico, Morabito, Fortunato, Carbone, Antonino, Gaidano, Gianluca, Malavasi, Fabio, and Deaglio, Silvia

Abstract

CD38 rules proliferation signals in chronic lymphocytic leukemia (CLL) cells, suggesting that the molecule is not merely a prognostic marker but also a key element in the pathogenetic network underlying the disease. CD38 has a genetic polymorphism, characterized by a C>G variation in the regulatory region of intron 1. The working hypothesis is that the presence of different alleles in CLL patients marks (or accounts for) some of the clinical heterogeneity. CD38allele distribution in 248 Italian patients overlapped with that of the controls (n = 232), suggesting that susceptibility to CLL is not influenced by CD38genotype. Stratification of patients according to markers of unfavorable prognosis constantly resulted in a significantly higher frequency of the rare G allele. Furthermore, analysis of clinical parameters showed that G allele is independently associated with nodal/splenic involvement. The highest G allele frequency was observed in the 16 patients of the cohort that developed Richter syndrome (RS). Five-year cumulative incidence of transformation was significantly higher in G allele carriers than in CC homozygotes. Multivariate analysis on a total of 30 RS patients confirmed that the probability of transformation is strongly associated with G allele, likely representing an independent risk factor for RS development.

Published
2008
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47. 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, Bredo-Pedersen, Lone, Tschumper, Renee C., Sutton, Lesley-Ann, Baliakas, Panagiotis, Scarfò, Lydia, van Gastel, Ellen J., Armand, Marine, Tausch, Eugen, Biderman, Bella, Baer, Constance, Bagnara, Davide, Navarro, Alba, Langlois de Septenville, Anne, Guido, Valentina, Mitterbauer-Hohendanner, Gerlinde, Dimovski, Aleksandar, Brieghel, Christian, Lawless, Sarah, Meggendorfer, Manja, Braazdilova, Kamila, Ritgen, Matthias, Facco, Monica, Tresoldi, Cristina, Visentin, Andrea, Patriarca, Andrea, Catherwood, Mark, Bonello, Lisa, Sudarikov, Andrey, Vanura, Katrina, Roumelioti, Maria, Skuhrova-Francova, Hana, Moysiadis, Theodoros, Veronese, Silvio, Giannopoulos, Krzysztof, Mansouri, Larry, Karan-Djurasevic, Teodora, Sandaltzopoulos, Raphael, Bödör, Csaba, Fais, Franco, Kater, Arnon, Panovska, Irina, Rossi, Davide, Alshemmari, Salem, Panagiotidis, Panagiotis, Costeas, Paul, Espinet Solà, Blanca, Antic, Darko, Foroni, Letizia, Montillo, Marco, Trentin, Livio, Stavroyianni, Niki, Gaidano, Gianluca, Francia di Celle, Paola, 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, Bredo-Pedersen, Lone, Tschumper, Renee C., Sutton, Lesley-Ann, Baliakas, Panagiotis, Scarfò, Lydia, van Gastel, Ellen J., Armand, Marine, Tausch, Eugen, Biderman, Bella, Baer, Constance, Bagnara, Davide, Navarro, Alba, Langlois de Septenville, Anne, Guido, Valentina, Mitterbauer-Hohendanner, Gerlinde, Dimovski, Aleksandar, Brieghel, Christian, Lawless, Sarah, Meggendorfer, Manja, Braazdilova, Kamila, Ritgen, Matthias, Facco, Monica, Tresoldi, Cristina, Visentin, Andrea, Patriarca, Andrea, Catherwood, Mark, Bonello, Lisa, Sudarikov, Andrey, Vanura, Katrina, Roumelioti, Maria, Skuhrova-Francova, Hana, Moysiadis, Theodoros, Veronese, Silvio, Giannopoulos, Krzysztof, Mansouri, Larry, Karan-Djurasevic, Teodora, Sandaltzopoulos, Raphael, Bödör, Csaba, Fais, Franco, Kater, Arnon, Panovska, Irina, Rossi, Davide, Alshemmari, Salem, Panagiotidis, Panagiotis, Costeas, Paul, Espinet Solà, Blanca, Antic, Darko, Foroni, Letizia, Montillo, Marco, Trentin, Livio, Stavroyianni, Niki, Gaidano, Gianluca, Francia di Celle, Paola, 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 immunoglobulins (BcR IG). Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR IG 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 IG stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. In order 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.

48. Higher-order connections between stereotyped subsets

Author

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

Subjects
Chronic lymphocytic leukemia, Immunology, B-cell receptor, Immunoglobulin Variable Region, Disease, Computational biology, Biology, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, hemic and lymphatic diseases, Immunoglobulin, medicine, Humans, Chronic, 030304 developmental biology, Gene Rearrangement, 0303 health sciences, Leukemia, Lymphoid Neoplasia, Repertoire, B-Cell, breakpoint cluster region, Cell Biology, Hematology, Gene rearrangement, Somatic Hypermutation, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphocytic, Stereotypy (non-human), Immunoglobulin Heavy Chains, Somatic Hypermutation, Immunoglobulin, 030220 oncology & carcinogenesis, IGHV@
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. Key Points: • In a series of 29 856 CLL patients, the incidence of BcR stereotypy peaked at 41%. • Higher-order relations exist between stereotyped subsets, particularly for those from U-CLL, for which satellite subsets were identified.

Published
2021
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49. HIF-1α is overexpressed in leukemic cells from TP53-disrupted patients and is a promising therapeutic target in chronic lymphocytic leukemia

Author

Riccardo Bomben, Paola Omedè, Marta Coscia, Robin Foà, Michele Dal Bo, Mario Boccadoro, Davide Rossi, Gabriele Pozzato, Daniela Magliulo, Giovanni Del Poeta, Valentina Griggio, Rosa Bernardi, Chiara Riganti, Francesca Romana Mauro, Maria Todaro, Gianluca Gaidano, Chiara Salvetti, Massimo Massaia, Joanna Kopecka, Lisa Bonello, Luca Laurenti, Candida Vitale, Thorsten Zenz, Valter Gattei, Monia Marchetti, Ahad Ahmed Kodipad, Griggio, Valentina, Vitale, Candida, Todaro, Maria, Riganti, Chiara, Kopecka, Joanna, Salvetti: Riccardo Bomben, Chiara, Dal Bo, Michele, Magliulo, Daniela, Rossi, Davide, Pozzato, Gabriele, Bonello, Lisa, Marchetti, Monia, Omedè, Paola, Ahmed Kodipad, Ahad, Laurenti, Luca, Del Poeta, Giovanni, Romana Mauro, Francesca, Bernardi, Rosa, Zenz, Thorsten, Gattei, Valter, Gaidano, Gianluca, Foà, Robin, Massaia, Massimo, Boccadoro, Mario, Coscia, Marta, and University of Zurich

Subjects
RHOA, Chronic lymphocytic leukemia, 2720 Hematology, chronic lymphocytic leukaemia, TP53-disruption, prognosis, p53 abnormalities, Mice, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Tumor Microenvironment, Chronic, B-Cell, Cytotoxic T cell, Chronic, Patient, Leukemia, biology, CLL microenvironment, Chemistry, Hematology, Lymphocytic, Editorial, Von Hippel-Lindau Tumor Suppressor Protein, Stromal cell, Patients, 610 Medicine & health, Chronic Lymphocytic Leukemia, Hypoxia inducible factor-1a, ibrutinib, Article, 03 medical and health sciences, medicine, Animals, Humans, Protein kinase B, PI3K/AKT/mTOR pathway, Tumor microenvironment, Lymphocytic leukemia, B-Cell, medicine.disease, Hypoxia-Inducible Factor 1, alpha Subunit, Settore MED/15, Leukemia, Lymphocytic, Chronic, B-Cell, Settore MED/15 - MALATTIE DEL SANGUE, 10032 Clinic for Oncology and Hematology, biology.protein, Cancer research, Tumor Suppressor Protein p53, 030215 immunology
Abstract

In chronic lymphocytic leukemia (CLL), the hypoxia-inducible factor 1 (HIF-1) regulates the response of tumor cells to hypoxia and their protective interactions with the leukemic microenvironment. In this study, we demonstrate that CLL cells from TP53-disrupted (TP53 dis) patients have constitutively higher expression levels of the α-subunit of HIF-1 (HIF-1α) and increased HIF-1 transcriptional activity compared to the wild-type counterpart. In the TP53 dis subset, HIF-1α upregulation is due to reduced expression of the HIF-1α ubiquitin ligase von Hippel-Lindau protein (pVHL). Hypoxia and stromal cells further enhance HIF-1α accumulation, independently of TP53 status. Hypoxia acts through the downmodulation of pVHL and the activation of the PI3K/AKT and RAS/ERK1-2 pathways, whereas stromal cells induce an increased activity of the RAS/ERK1-2, RHOA/RHOA kinase and PI3K/AKT pathways, without affecting pVHL expression. Interestingly, we observed that higher levels of HIF-1A mRNA correlate with a lower susceptibility of leukemic cells to spontaneous apoptosis, and associate with the fludarabine resistance that mainly characterizes TP53 dis tumor cells. The HIF-1α inhibitor BAY87-2243 exerts cytotoxic effects toward leukemic cells, regardless of the TP53 status, and has anti-tumor activity in Em-TCL1 mice. BAY87-2243 also overcomes the constitutive fludarabine resistance of TP53 dis leukemic cells and elicits a strongly synergistic cytotoxic effect in combination with ibrutinib, thus providing preclinical evidence to stimulate further investigation into use as a potential new drug in CLL.

Published
2019

50. HIF-1α is over-expressed in leukemic cells from TP53 -disrupted patients and is a promising therapeutic target in chronic lymphocytic leukemia.

Author

Griggio V, Vitale C, Todaro M, Riganti C, Kopecka J, Salvetti C, Bomben R, Bo MD, Magliulo D, Rossi D, Pozzato G, Bonello L, Marchetti M, Omedè P, Kodipad AA, Laurenti L, Del Poeta G, Mauro FR, Bernardi R, Zenz T, Gattei V, Gaidano G, Foà R, Massaia M, Boccadoro M, and Coscia M

Subjects
Animals, Humans, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Mice, Phosphatidylinositol 3-Kinases genetics, Tumor Microenvironment, Tumor Suppressor Protein p53 genetics, Von Hippel-Lindau Tumor Suppressor Protein, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics
Abstract

In chronic lymphocytic leukemia (CLL), the hypoxia-inducible factor 1 (HIF-1) regulates the response of tumor cells to hypoxia and their protective interactions with the leukemic microenvironment. In this study, we demonstrate that CLL cells from TP53 -disrupted ( TP53 dis ) patients have constitutively higher expression levels of the α-subunit of HIF-1 (HIF-1α) and increased HIF-1 transcriptional activity compared to the wild-type counterpart. In the TP53 dis subset, HIF-1α upregulation is due to reduced expression of the HIF-1α ubiquitin ligase von Hippel-Lindau protein (pVHL). Hypoxia and stromal cells further enhance HIF-1α accumulation, independently of TP53 status. Hypoxia acts through the downmodulation of pVHL and the activation of the PI3K/AKT and RAS/ERK1-2 pathways, whereas stromal cells induce an increased activity of the RAS/ERK1-2, RHOA/RHOA kinase and PI3K/AKT pathways, without affecting pVHL expression. Interestingly, we observed that higher levels of HIF-1A mRNA correlate with a lower susceptibility of leukemic cells to spontaneous apoptosis, and associate with the fludarabine resistance that mainly characterizes TP53 dis tumor cells. The HIF-1α inhibitor BAY87-2243 exerts cytotoxic effects toward leukemic cells, regardless of the TP53 status, and has anti-tumor activity in Em-TCL1 mice. BAY87-2243 also overcomes the constitutive fludarabine resistance of TP53 dis leukemic cells and elicits a strongly synergistic cytotoxic effect in combination with ibrutinib, thus providing preclinical evidence to stimulate further investigation into use as a potential new drug in CLL., (Copyright© 2020 Ferrata Storti Foundation.)

Published
2020
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