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1. Recurrent somatic mutations of FAT family cadherins induce an aggressive phenotype and poor prognosis in anaplastic large cell lymphoma

Author

Villa, Matteo, Sharma, Geeta G., Malighetti, Federica, Mauri, Mario, Arosio, Giulia, Cordani, Nicoletta, Lobello, Cosimo, Larose, Hugo, Pirola, Alessandra, D’Aliberti, Deborah, Massimino, Luca, Criscuolo, Lucrezia, Pagani, Lisa, Chinello, Clizia, Mastini, Cristina, Fontana, Diletta, Bombelli, Silvia, Meneveri, Raffaella, Lovisa, Federica, Mussolin, Lara, Janikova, Andrea, Pospíšilová, Šárka, Turner, Suzanne D., Inghirami, Giorgio, Magni, Fulvio, Urso, Mario, Pagni, Fabio, Ramazzotti, Daniele, Piazza, Rocco, Chiarle, Roberto, Gambacorti-Passerini, Carlo, and Mologni, Luca

Published
2024
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5. Quantitative assessment of minimal residual disease for monitoring of paediatric patients with relapsed/refractory anaplastic large‐cell lymphoma treated with brentuximab vedotin: A case series.

Author

Contarini, Giorgia, Carraro, Elisa, Lovisa, Federica, Martire, Gaia, Lo Nigro, Luca, Sala, Alessandra, Pillon, Marta, and Mussolin, Lara

Subjects
ANAPLASTIC large-cell lymphoma, CHILD patients, POSITRON emission tomography computed tomography, PATIENT monitoring, HODGKIN'S disease, ANAPLASTIC thyroid cancer
Abstract

This article discusses the use of brentuximab vedotin (BV) for the treatment of relapsed or refractory anaplastic large-cell lymphoma (ALCL) in pediatric patients. The study focuses on the role of minimal residual disease (MRD) monitoring using droplet digital PCR (dPCR) to assess treatment response and predict relapse. The results suggest that multiple cycles of BV are necessary to achieve complete remission, and MRD positivity may serve as an early indicator of relapse. The study acknowledges its limitations due to its retrospective nature and small sample size. The research was supported by various funding sources and the authors declare no conflicts of interest. [Extracted from the article]

Published
2024
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7. Single-cell transcriptomics of pediatric Burkitt lymphoma reveals intra-tumor heterogeneity and markers of therapy resistance

Author

Corinaldesi, Clarissa, Holmes, Antony B., Martire, Gaia, Tosato, Anna, Rizzato, Domenico, Lovisa, Federica, Gallingani, Ilaria, Shen, Qiong, Ferrone, Lavinia, Harris, Marian, Davies, Kimberly, Molinaro, Luca, Mortara, Umberto, Dei Tos, Angelo Paolo, Ofori, Kenneth, D’Amore, Emanuele S. G., Chiarle, Roberto, Ngan, Bo, Carraro, Elisa, Pillon, Marta, Hussein, Shafinaz, Bhagat, Govind, Pizzi, Marco, Mussolin, Lara, and Basso, Katia

Abstract

Burkitt lymphoma (BL) is the most frequent B-cell lymphoma in pediatric patients. While most patients are cured, a fraction of them are resistant to therapy. To investigate BL heterogeneity and the features distinguishing therapy responders (R) from non-responders (NR), we analyzed by single-cell (sc)-transcriptomics diagnostic EBV-negative BL specimens. Analysis of the non-tumor component revealed a predominance of immune cells and a small representation of fibroblasts, enriched in NR. Tumors displayed patient-specific features, as well as shared subpopulations that expressed transcripts related to cell cycle, signaling pathways and cell-of-origin signatures. Several transcripts were differentially expressed in R versus NR. The top candidate, Tropomyosin 2 (TPM2), a member of the tropomyosin actin filament binding protein family, was confirmed to be significantly higher in NR both at the transcript and protein level. Stratification of patients based on TPM2 expression at diagnosis significantly correlated with prognosis, independently of TP53mutations. These results indicate that BL displays transcriptional heterogeneity and identify candidate biomarkers of therapy resistance.

Published
2024
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8. Plasma small‐extracellular vesicles enriched in miR‐122‐5p promote disease aggressiveness in pediatric anaplastic large‐cell lymphoma.

Author

Damanti, Carlotta Caterina, Ferrone, Lavinia, Gaffo, Enrico, Garbin, Anna, Tosato, Anna, Contarini, Giorgia, Gallingani, Ilaria, Angioni, Roberta, Molon, Barbara, Borile, Giulia, Carraro, Elisa, Pillon, Marta, Scarmozzino, Federico, Dei Tos, Angelo Paolo, Pizzi, Marco, Ciscato, Francesco, Rasola, Andrea, Biffi, Alessandra, Bortoluzzi, Stefania, and Lovisa, Federica

Published
2023
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9. Phosphoproteomic Analysis Reveals a Different Proteomic Profile in Pediatric Patients With T-Cell Lymphoblastic Lymphoma or T-Cell Acute Lymphoblastic Leukemia

Author

Veltri, Giulia, primary, Lovisa, Federica, additional, Cortese, Giuliana, additional, Pillon, Marta, additional, Carraro, Elisa, additional, Cesaro, Simone, additional, Provenzi, Massimo, additional, Buffardi, Salvatore, additional, Francescato, Samuela, additional, Biffi, Alessandra, additional, Buldini, Barbara, additional, Conter, Valentino, additional, Serafin, Valentina, additional, and Mussolin, Lara, additional

Published
2022
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10. Quantification of Minimal Disease by Digital PCR in ALK-Positive Anaplastic Large Cell Lymphoma: A Step towards Risk Stratification in International Trials?

Author

Damm-Welk, Christine, primary, Lovisa, Federica, additional, Contarini, Giorgia, additional, Lüdersen, Jette, additional, Carraro, Elisa, additional, Knörr, Fabian, additional, Förster, Jan, additional, Zimmermann, Martin, additional, Sala, Alessandra, additional, Vinti, Luciana, additional, Tondo, Annalisa, additional, Pillon, Marta, additional, Woessmann, Wilhelm, additional, and Mussolin, Lara, additional

Published
2022
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13. Synergistic Drug Combinations Prevent Resistance in ALK+ Anaplastic Large Cell Lymphoma

Author

Arosio, Giulia, primary, Sharma, Geeta G., additional, Villa, Matteo, additional, Mauri, Mario, additional, Crespiatico, Ilaria, additional, Fontana, Diletta, additional, Manfroni, Chiara, additional, Mastini, Cristina, additional, Zappa, Marina, additional, Magistroni, Vera, additional, Ceccon, Monica, additional, Redaelli, Sara, additional, Massimino, Luca, additional, Garbin, Anna, additional, Lovisa, Federica, additional, Mussolin, Lara, additional, Piazza, Rocco, additional, Gambacorti-Passerini, Carlo, additional, and Mologni, Luca, additional

Published
2021
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14. Prognostic Role of Minimal Disseminated Disease and NOTCH1/FBXW7 Mutational Status in Children with Lymphoblastic Lymphoma: The AIEOP Experience

Author

Lovisa, Federica, primary, Gallingani, Ilaria, additional, Varotto, Elena, additional, Pasin, Cristiano, additional, Carraro, Elisa, additional, Michielotto, Barbara, additional, Garbin, Anna, additional, Damanti, Carlotta Caterina, additional, Pizzi, Marco, additional, d’Amore, Emanuele S. G., additional, Piglione, Matilde, additional, Muggeo, Paola, additional, Buffardi, Salvatore, additional, Vinti, Luciana, additional, Folsi, Veronica Maria, additional, Onofrillo, Daniela, additional, Biffi, Alessandra, additional, Buldini, Barbara, additional, Pillon, Marta, additional, and Mussolin, Lara, additional

Published
2021
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16. Ruxolitinib as a Novel Therapeutic Option for Poor Prognosis T-LBL Pediatric Patients

Author

Veltri, Giulia, primary, Silvestri, Chiara, additional, Gallingani, Ilaria, additional, Sandei, Max, additional, Vencato, Sara, additional, Lovisa, Federica, additional, Cortese, Giuliana, additional, Pillon, Marta, additional, Carraro, Elisa, additional, Bresolin, Silvia, additional, Biffi, Alessandra, additional, Basso, Giuseppe, additional, Accordi, Benedetta, additional, Mussolin, Lara, additional, and Serafin, Valentina, additional

Published
2021
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17. Abstract 1113: Synergistic drug combinations prevent drug resistance in anaplastic large cell lymphoma preclinical models

Author

Sharma, Geeta G., primary, Arosio, Giulia, additional, Villa, Matteo, additional, Mauri, Mario, additional, Zappa, Marina, additional, Magistroni, Vera, additional, Ceccon, Monica, additional, Redaelli, Sara, additional, Crespiatico, Ilaria, additional, Fontana, Diletta, additional, Mastini, Cristina, additional, Garbin, Anna, additional, Lovisa, Federica, additional, Mussolin, Lara, additional, Piazza, Rocco, additional, Gambacorrti-Passerini, Carlo, additional, and Mologni, Luca, additional

Published
2021
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18. Low miR-214-5p Expression Correlates With Aggressive Subtypes of Pediatric ALCL With Non-Common Histology

Author

Di Battista, Piero, primary, Lovisa, Federica, additional, Gaffo, Enrico, additional, Gallingani, Ilaria, additional, Damanti, Carlotta C., additional, Garbin, Anna, additional, Ferrone, Lavinia, additional, Carraro, Elisa, additional, Pillon, Marta, additional, Lo Nigro, Luca, additional, Mura, Rossella, additional, Pizzi, Marco, additional, Guzzardo, Vincenza, additional, Dei Tos, Angelo Paolo, additional, Biffi, Alessandra, additional, Bortoluzzi, Stefania, additional, and Mussolin, Lara, additional

Published
2021
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19. Proteomic Exploration of Plasma Exosomes and Other Small Extracellular Vesicles in Pediatric Hodgkin Lymphoma: A Potential Source of Biomarkers for Relapse Occurrence

Author

Repetto, Ombretta, primary, Lovisa, Federica, additional, Elia, Caterina, additional, Enderle, Daniel, additional, Romanato, Filippo, additional, Buffardi, Salvatore, additional, Sala, Alessandra, additional, Pillon, Marta, additional, Steffan, Agostino, additional, Burnelli, Roberta, additional, Mussolin, Lara, additional, Mascarin, Maurizio, additional, and De Re, Valli, additional

Published
2021
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20. Droplet Digital PCR Improves IG-/TR-based MRD Risk Definition in Childhood B-cell Precursor Acute Lymphoblastic Leukemia

Author

Della Starza, I, Nunes, V, Lovisa, F, Silvestri, D, Cavalli, M, Garofalo, A, Campeggio, M, De Novi, L, Soscia, R, Oggioni, C, Mussolin, L, Biondi, A, Guarini, A, Valsecchi, M, Conter, V, Biffi, A, Basso, G, Foà, R, Cazzaniga, G, Della Starza, Irene, Nunes, Vittorio, Lovisa, Federica, Silvestri, Daniela, Cavalli, Marzia, Garofalo, Andrea, Campeggio, Mimma, De Novi, Lucia Anna, Soscia, Roberta, Oggioni, Carlotta, Mussolin, Lara, Biondi, Andrea, Guarini, Anna, Valsecchi, Maria Grazia, Conter, Valentino, Biffi, Alessandra, Basso, Giuseppe, Foà, Robin, Cazzaniga, Giovanni, Della Starza, I, Nunes, V, Lovisa, F, Silvestri, D, Cavalli, M, Garofalo, A, Campeggio, M, De Novi, L, Soscia, R, Oggioni, C, Mussolin, L, Biondi, A, Guarini, A, Valsecchi, M, Conter, V, Biffi, A, Basso, G, Foà, R, Cazzaniga, G, Della Starza, Irene, Nunes, Vittorio, Lovisa, Federica, Silvestri, Daniela, Cavalli, Marzia, Garofalo, Andrea, Campeggio, Mimma, De Novi, Lucia Anna, Soscia, Roberta, Oggioni, Carlotta, Mussolin, Lara, Biondi, Andrea, Guarini, Anna, Valsecchi, Maria Grazia, Conter, Valentino, Biffi, Alessandra, Basso, Giuseppe, Foà, Robin, and Cazzaniga, Giovanni

Abstract

Minimal residual disease (MRD) is the most powerful prognostic factor in pediatric acute lymphoblastic leukemia (ALL). Real-time quantitative polymerase chain reaction (RQ-PCR) represents the gold standard for molecular MRD assessment and risk-based stratification of front-line treatment. In the protocols of the Italian Association of Pediatric Hematology and Oncology (AIEOP) and the Berlin-Frankfurth-Munschen (BFM) group AIEOP-BFM ALL2009 and ALL2017, B-lineage ALL patients with high RQ-PCR-MRD at day+33 and positive at day+78 are defined slow early responders (SERs). Based on results of the AIEOP-BFM ALL2000 study, these patients are treated as high-risk also when positive MRD signal at day +78 is below the lower limit of quantification of RQ-PCR ("positive not-quantifiable," POS-NQ). To assess whether droplet digital polymerase chain reaction (ddPCR) could improve patients' risk definition, we analyzed MRD in 209 pediatric B-lineage ALL cases classified by RQ-PCR as POS-NQ and/or negative (NEG) at days +33 and/or +78 in the AIEOP-BFM ALL2000 trial. ddPCR MRD analysis was performed on 45 samples collected at day +78 from SER patients, who had RQ-PCR MRD ≥ 5.0 * 10-4 at day+33 and POS-NQ at day+78 and were treated as medium risk (MR). The analysis identified 13 of 45 positive quantifiable cases. Most relapses occurred in this patients' subgroup, while ddPCR NEG or ddPCR-POS-NQ patients had a significantly better outcome (P < 0.001). Overall, in 112 MR cases and 52 standard-risk patients, MRD negativity and POS-NQ were confirmed by the ddPCR analysis except for a minority of cases, for whom no differences in outcome were registered. These data indicate that ddPCR is more accurate than RQ-PCR in the measurement of MRD, particularly in late follow-up time points, and may thus allow improving patients' stratification in ALL protocols.

Published
2021

21. Droplet Digital PCR Improves IG-/TR-based MRD Risk Definition in Childhood B-cell Precursor Acute Lymphoblastic Leukemia

Author

Della Starza, Irene, primary, Nunes, Vittorio, additional, Lovisa, Federica, additional, Silvestri, Daniela, additional, Cavalli, Marzia, additional, Garofalo, Andrea, additional, Campeggio, Mimma, additional, De Novi, Lucia Anna, additional, Soscia, Roberta, additional, Oggioni, Carlotta, additional, Mussolin, Lara, additional, Biondi, Andrea, additional, Guarini, Anna, additional, Valsecchi, Maria Grazia, additional, Conter, Valentino, additional, Biffi, Alessandra, additional, Basso, Giuseppe, additional, Foà, Robin, additional, and Cazzaniga, Giovanni, additional

Published
2021
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22. Increased Tenascin C, Osteopontin and HSP90 Levels in Plasmatic Small Extracellular Vesicles of Pediatric ALK-Positive Anaplastic Large Cell Lymphoma: New Prognostic Biomarkers?

Author

Lovisa, Federica, primary, Garbin, Anna, additional, Crotti, Sara, additional, Di Battista, Piero, additional, Gallingani, Ilaria, additional, Damanti, Carlotta Caterina, additional, Tosato, Anna, additional, Carraro, Elisa, additional, Pillon, Marta, additional, Mafakheri, Erfan, additional, Romanato, Filippo, additional, Gaffo, Enrico, additional, Biffi, Alessandra, additional, Bortoluzzi, Stefania, additional, Agostini, Marco, additional, and Mussolin, Lara, additional

Published
2021
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23. MiR-26a-5p as a Reference to Normalize MicroRNA qRT-PCR Levels in Plasma Exosomes of Pediatric Hematological Malignancies

Author

Damanti, Carlotta C., primary, Gaffo, Enrico, additional, Lovisa, Federica, additional, Garbin, Anna, additional, Di Battista, Piero, additional, Gallingani, Ilaria, additional, Tosato, Anna, additional, Pillon, Marta, additional, Carraro, Elisa, additional, Mascarin, Maurizio, additional, Elia, Caterina, additional, Biffi, Alessandra, additional, Bortoluzzi, Stefania, additional, and Mussolin, Lara, additional

Published
2021
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27. Minimal residual disease analysis in childhood mature B‐cell leukaemia/lymphoma treated with AIEOP LNH‐97 protocol with/without anti‐CD20 administration

Author

Mussolin, Lara, primary, Lovisa, Federica, additional, Gallingani, Ilaria, additional, Cavallaro, Elena, additional, Carraro, Elisa, additional, Damanti, Carlotta C., additional, Vinti, Luciana, additional, Sala, Alessandra, additional, Micalizzi, Concetta, additional, Santoro, Nicola, additional, Piglione, Matilde, additional, Cellini, Monica, additional, Buffardi, Salvatore, additional, Buldini, Barbara, additional, D’Amore, Emanuele S. G., additional, Biffi, Alessandra, additional, and Pillon, Marta, additional

Published
2020
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28. A high definition picture of key genes and pathways mutated in pediatric follicular lymphoma

Author

Lovisa, Federica, primary, Binatti, Andrea, additional, Coppe, Alessandro, additional, Primerano, Simona, additional, Carraro, Elisa, additional, Pillon, Marta, additional, Pizzi, Marco, additional, Guzzardo, Vincenza, additional, Buffardi, Salvatore, additional, Porta, Fulvio, additional, Farruggia, Piero, additional, De Santis, Raffaela, additional, Bulian, Pietro, additional, Basso, Giuseppe, additional, Lazzari, Elena, additional, d’Amore, Emanuele S.G., additional, Bortoluzzi, Stefania, additional, and Mussolin, Lara, additional

Published
2019
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29. Digital-Droplet PCR, an Accurate Method for IG/TR PCR-MRD Stratification in Childhood Acute Lymphoblastic Leukemia

Author

Della Starza, Irene, primary, Nunes, Vittorio, additional, Lovisa, Federica, additional, Silvestri, Daniela, additional, Cavalli, Marzia, additional, Garofalo, Andrea, additional, Campeggio, Mimma, additional, De Novi, Lucia Anna, additional, Oggioni, Carlotta, additional, Biondi, Andrea, additional, Guarini, Anna, additional, Valsecchi, Maria Grazia, additional, Conter, Valentino, additional, Basso, Giuseppe, additional, Foà, Robin, additional, and Cazzaniga, Giovanni, additional

Published
2018
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30. Pre-clinical evaluation of second generation PIM inhibitors for the treatment of T-cell acute lymphoblastic leukemia and lymphoma

Author

De Smedt, Renate, primary, Peirs, Sofie, additional, Morscio, Julie, additional, Matthijssens, Filip, additional, Roels, Juliette, additional, Reunes, Lindy, additional, Lintermans, Beatrice, additional, Goossens, Steven, additional, Lammens, Tim, additional, Van Roy, Nadine, additional, Touzart, Aurore, additional, Jenni, Silvia, additional, Tsai, Yi-Chien, additional, Lovisa, Federica, additional, Mussolin, Lara, additional, Serafin, Valentina, additional, Van Nieuwerburgh, Filip, additional, Deforce, Dieter, additional, Uyttebroeck, Anne, additional, Tousseyn, Thomas, additional, Burkhardt, Birgit, additional, Klapper, Wolfram, additional, De Moerloose, Barbara, additional, Benoit, Yves, additional, Macintyre, Elizabeth, additional, Bourquin, Jean-Pierre, additional, Basso, Giuseppe, additional, Accordi, Benedetta, additional, Bornhauser, Beat, additional, Meijerink, Jules, additional, Vandenberghe, Peter, additional, and Van Vlierberghe, Pieter, additional

Published
2018
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31. Pre- and post-transplant minimal residual disease predicts relapse occurrence in children with acute lymphoblastic leukaemia

Author

Lovisa, F, Zecca, M, Rossi, B, Campeggio, M, Magrin, E, Giarin, E, Buldini, B, Songia, S, Cazzaniga, G, Mina, T, Acquafredda, G, Quarello, P, Locatelli, F, Fagioli, F, Basso, G, Lovisa, Federica, Zecca, Marco, Rossi, Bartolomeo, Campeggio, Mimma, Magrin, Elisa, Giarin, Emanuela, Buldini, Barbara, Songia, Simona, Cazzaniga, Giovanni, Mina, Tommaso, Acquafredda, Gloria, Quarello, Paola, Locatelli, Franco, Fagioli, Franca, Basso, Giuseppe, Lovisa, F, Zecca, M, Rossi, B, Campeggio, M, Magrin, E, Giarin, E, Buldini, B, Songia, S, Cazzaniga, G, Mina, T, Acquafredda, G, Quarello, P, Locatelli, F, Fagioli, F, Basso, G, Lovisa, Federica, Zecca, Marco, Rossi, Bartolomeo, Campeggio, Mimma, Magrin, Elisa, Giarin, Emanuela, Buldini, Barbara, Songia, Simona, Cazzaniga, Giovanni, Mina, Tommaso, Acquafredda, Gloria, Quarello, Paola, Locatelli, Franco, Fagioli, Franca, and Basso, Giuseppe

Abstract

Relapse remains the leading cause of treatment failure in children with acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem cell transplantation (HSCT). We retrospectively investigated the prognostic role of minimal residual disease (MRD) before and after HSCT in 119 children transplanted in complete remission (CR). MRD was measured by polymerase chain reaction in bone marrow samples collected pre-HSCT and during the first and third trimesters after HSCT (post-HSCT1 and post-HSCT3). The overall event-free survival (EFS) was 50%. The cumulative incidence of relapse and non-relapse mortality was 41% and 9%. Any degree of detectable pre-HSCT MRD was associated with poor outcome: EFS was 39% and 18% in patients with MRD positivity <1 × 10−3 and ≥1 × 10−3, respectively, versus 73% in MRD-negative patients (P < 0·001). This effect was maintained in different disease remissions, but low-level MRD had a very strong negative impact only in patients transplanted in second or further CR. Also, MRD after HSCT enabled patients to be stratified, with increasing MRD between post-HSCT1 and post-HSCT3 clearly defining cohorts with a different outcome. MRD is an important prognostic factor both before and after transplantation. Given that MRD persistence after HSCT is associated with dismal outcome, these patients could benefit from early discontinuation of immunosuppression, or pre-emptive immuno-therapy

Published
2018

32. Comparison of MRD detection by RQ-PCR and droplet digital PCRin pediatric Acute Lymphoblastic Leukemia before Hematopoietic Stem Cell Transplantation

Author

Campeggio, Mimma, Trentin, Luca, Camnasio, Sheila, Giarin, Emanuela, Buldini, Barbara, Carraro, Elisa, Pillon, Marta, Simona, Songia, Gianni, Cazzaniga, Basso, Giuseppe, and Lovisa, Federica

Subjects
Minimal Residual Disease, children, Haematopoietic Stem Cell Transplantation, droplet digital PCR, Minimal Residual Disease, Acute Lymphoblastic Leukemia, children, Haematopoietic Stem Cell Transplantation, Acute Lymphoblastic Leukemia, droplet digital PCR
Published
2017

33. Applicazione Della Droplet Digital Pcr Per La Quantificazione Della Malattia Residua Minima Nella Leucemia Linfoblastica Acuta Pediatrica

Author

Campeggio, Mimma, Trentin, Luca, Camnasio, Sheila, Giarin, Emanuela, Simona, Songia, Gianni, Cazzaniga, Basso, Giuseppe, and Lovisa, Federica

Subjects
Malattia Residua Minima, Leucemia Linfoblastica Acuta Pediatrica, Droplet Digital Pcr, Malattia Residua Minima, Leucemia Linfoblastica Acuta Pediatrica, Trapianto Cellule Staminali Ematopoietiche, Droplet Digital Pcr, Trapianto Cellule Staminali Ematopoietiche
Published
2016

34. Clinical impact of miR-223 expression in pediatric T-Cell lymphoblastic lymphoma

Author

Pomari, Elena, primary, Lovisa, Federica, additional, Carraro, Elisa, additional, Primerano, Simona, additional, D’Amore, Emanuele S.G., additional, Bonvini, Paolo, additional, Nigro, Luca Lo, additional, Vito, Rita De, additional, Vinti, Luciana, additional, Farruggia, Piero, additional, Pillon, Marta, additional, Basso, Giuseppe, additional, Basso, Katia, additional, and Mussolin, Lara, additional

Published
2017
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38. Ultra-deep mutational analysis of NPM-ALK and possible implications on target therapy in anaplastic large cell lymphoma of childhood

Author

Lovisa, Federica

Subjects
Settore MED/38 - Pediatria Generale e Specialistica, crizotinib, target therapy, hemic and lymphatic diseases, MED/38 Pediatria generale e specialistica, kinase inhibitors, NPM-ALK, ALCL, crizotinib, target therapy, kinase inhibitors, mutation, next-generation sequencing, next-generation sequencing, NPM-ALK, mutation, ALCL
Abstract

Anaplastic Large Cell Lymphoma (ALCL) represents a distinct subset of aggressive T-cell non-Hodgkin lymphoma (NHL) accounting for about 3% of adult NHL and 10 to 15% of childhood lymphomas. In the vast majority of the cases, ALCL is associated to chromosomal translocations, the most frequent being the t(2;5)(p23;q35), involving the Anaplastic Lymphoma Kinase (ALK) gene, which lead to aberrant NPM-ALK protein expression and kinase activity. It has been extensively demonstrated that aberrant NPM-ALK expression contributes to the pathogenesis of ALK-positive ALCL, as it causes cell transformation through activation of several biological pathways related to cell proliferation, cell-cycle control and apoptosis. Although ALK-positive ALCL have a rather benign prognosis when treated with standard chemotherapy, the failure rate at two years is almost 30% for most of these regimens. Notably, most of relapses occur within the first year from the start of therapy, and long-term survival for relapsed disease is less than 50%. Aberrant ALK activity is one of the major oncogenic events not only in ALK-positive ALCL, but also in neuroblastoma, non-small cell lung cancer (NSCLC) and inflammatory myofibroblastic tumour (IMT) bearing ALK activating mutations/rearrangements, and the inhibition of ALK kinase activity was proven to substantially reduce cancer cell proliferation and invasiveness both in vitro and in vivo. Successful clinical experience with crizotinib further support the concept of ALK-specific inhibition as a valuable treatment strategy in ALK-positive ALCL, as well as in other ALK-addicted tumours. However, similarly to other inhibitors selectively targeting oncogenic kinases, data on relapse to crizotinib due to newly acquired secondary mutations were reported. In this context, although a robust clinical response of ALCL patients to an ALK inhibitor is expected, some of those patients are also anticipated to develop resistance, making the knowledge of NPM-ALK kinase domain (KD) mutational status a valuable and mandatory information to the rational design of ALK-targeted therapies. To detect somatic tumour mutations with potential utility for predicting treatment response in ALK-positive ALCL patients, we performed ultra-deep sequencing analysis on ALK exons 22-25, corresponding to the entire KD coding region, in 37 ALCL pediatric patients. Two low frequent point mutations were identified in two distinct cases, corresponding to the R1275Q and R1231Q amino acid changes. The R1275Q mutation has been already reported as one of the most frequent activating mutations in neuroblastoma, while the R1231Q amino acid substitution represents a novel ALK point mutation, which to our knowledge has never been reported neither in ALK receptor nor in other ALK-translocated kinases. The molecular implications of R1275Q and R1231Q point substitutions on NPM-ALK function and sensitivity to ALK-specific inhibition are still under our investigation. In addition to point mutation, oncokinase alternative spliced transcripts have been previously reported in patients with Bcr-Abl positive chronic myeloid leukemia and more recently ALK receptor isoforms were described in neuroblastoma. To our knowledge, however, NPM-ALK alternative splicing events have never been described. For the first time, we identified and characterized 9 NPM-ALK INDEL mutations, resulting from KD whole exons skipping or alternative canonical splicing sites recognition. To investigate the effect of INDEL mutations on the structure and activity of NPM-ALK, we performed molecular homology modelling and in vitro functional analysis. While all these mutants were shown to be kinase dead, we demonstrated that, when coespressed with wild-type NPM-ALK, these INDELs do interact with wild-type monomers and are likely to inhibit ALK kinase activity and increase sensitivity to treatment with crizotinib. This work demonstrates that NPM-ALK KD point mutations are extremely rare in newly diagnosed ALCL patients, but positive selection of mutated cells could not be excluded in case of an ALK-targeting therapy. Conversely, our results suggest that alternative splicing in NPM-ALK may represent a common event. A clear correlation between the presence of these variants and outcome could not be detected, possibly because of the restricted cohort of patients analyzed. However, we hypothesize that a significant impact of these mutations could be observed if an ALK-specific treatment is used. Patients bearing a consistent level of inactive NPM-ALK are therefore expected to respond differently to ALK kinase inhibitors; whether such a response will be increased or decreased, it remains to be elucidated.

Published
2013

41. ALK Kinase Domain Mutations in Primary Anaplastic Large Cell Lymphoma: Consequences on NPM-ALK Activity and Sensitivity to Tyrosine Kinase Inhibitors

Author

Lovisa, Federica, primary, Cozza, Giorgio, additional, Cristiani, Andrea, additional, Cuzzolin, Alberto, additional, Albiero, Alessandro, additional, Mussolin, Lara, additional, Pillon, Marta, additional, Moro, Stefano, additional, Basso, Giuseppe, additional, Rosolen, Angelo, additional, and Bonvini, Paolo, additional

Published
2015
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45. Small RNAs in Circulating Exosomes of Cancer Patients: A Minireview.

Author

Bortoluzzi, Stefania, Lovisa, Federica, Gaffo, Enrico, and Mussolin, Lara

Subjects
*NON-coding RNA, *EXOSOMES, *CANCER patients
Abstract

Extracellular vesicles (EVs) secreted from many cell types play important roles in intercellular communication, both as paracrine and endocrine factors, as they can circulate in biological fluids, including plasma. Amid EVs, exosomes are actively secreted vesicles that contain proteins, lipids, soluble factors, and nucleic acids, including microRNAs (miRNAs) and other classes of small RNAs (sRNA). miRNAs are prominent post-transcriptional regulators of gene expression and epigenetic silencers of transcription. We concisely review the roles of miRNAs in cell-fate determination and development and their regulatory activity on almost all the processes and pathways controlling tumor formation and progression. Next, we consider the evidence linking exosomes to tumor progression, particularly to the setting-up of permissive pre-metastatic niches. The study of exosomes in patients with different survival and therapy response can inform on the possible correlations between exosomal cargo and disease features. Moreover, the exploration of circulating exosomes as possible sources of non-invasive biomarkers could give new implements for anti-cancer therapy and metastasis prevention. Since the characterization of sRNAs in exosomes of cancer patients sparks opportunities to better understand their roles in cancer, we briefly present current experimental and computational protocols for sRNAs analysis in circulating exosomes by RNA-seq. [ABSTRACT FROM AUTHOR]

Published
2017
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46. IGH and IGK gene rearrangements as PCR targets for pediatric Burkitt's lymphoma and mature B-ALL MRD analysis

Author

Lovisa, F, Mussolin, L, Corral, L, Pillon, M, Cazzaniga, G, Biondi, A, Rosolen, A, Lovisa, Federica, Mussolin, Lara, Corral, Lilia, Pillon, Marta, Cazzaniga, Giovanni, Biondi, Andrea, Rosolen, Angelo, Lovisa, F, Mussolin, L, Corral, L, Pillon, M, Cazzaniga, G, Biondi, A, Rosolen, A, Lovisa, Federica, Mussolin, Lara, Corral, Lilia, Pillon, Marta, Cazzaniga, Giovanni, Biondi, Andrea, and Rosolen, Angelo

Abstract

We recently reported that minimal residual disease (MRD) and minimal disseminated disease (MDD), assessed by long-distance PCR (LD-PCR) for t(8;14), are negative prognostic factors in mature B-cell acute lymphoblastic leukemia (B-ALL) and in Burkitt's lymphoma (BL). However, t(8;14) is detectable in only about 70% of patients, thus preventing MRD studies by this approach in the remaining patients. At present, no molecular assays have been reported for MRD and MDD analysis in t(8;14)-negative patients. The aim of our study was to evaluate the characteristics of patient-specific immunoglobulin (Ig) gene rearrangements as RQ-PCR targets for MRD analysis, in order to extend MRD studies to those patients who are not eligible for the LD-PCR assay. The study was performed according to the guidelines of the European Study Group on MRD detection in ALL (ESG-MRD-ALL). Overall, 36 B-ALL and 19 BL cases were analyzed. Multiple PCR reactions were performed for each sample to identify heavy and kappa light-chain rearrangements. A total of 97 RQ-PCR targets (62 for B-ALL, 35 for BL) were analyzed for sensitivity. The rearrangement pattern identified was similar to that reported for normal peripheral blood lymphocytes. In 88% of the targets, a sensitivity of at least 10(-4) was achieved. In 87% of patients (84% of B-ALLs, 95% of BLs) at least one sensitive target was available. All PCR targets identified at diagnosis were preserved at relapse. Our results suggest that MDD and MRD can be successfully studied using a single sensitive Ig target in the great majority of B-ALL and BL cases. The combination of LD-PCR and Ig-based assays will allow MRD analysis in virtually all of the patients.

Published
2009

47. TP53 DNA binding domain mutational status and rituximabbased treatment are independent prognostic factors for pediatric Burkitt lymphoma patients stratification.

Author

Martire G, Lovisa F, Carraro E, Rizzato D, Cesaro S, Mura RM, Tondo A, Bertolin C, Boaretto F, Salviati L, Biffi A, Pillon M, and Mussolin L

Subjects
Humans, Child, Prognosis, Male, Female, Child, Preschool, Adolescent, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Rituximab therapeutic use, Burkitt Lymphoma genetics, Burkitt Lymphoma drug therapy, Burkitt Lymphoma mortality, Burkitt Lymphoma diagnosis, Mutation, Tumor Suppressor Protein p53 genetics
Published
2024
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48. miR-939 acts as tumor suppressor by modulating JUNB transcriptional activity in pediatric anaplastic large cell lymphoma.

Author

Garbin A, Lovisa F, Holmes AB, Damanti CC, Gallingani I, Carraro E, Accordi B, Veltri G, Pizzi M, d'Amore ESG, Pillon M, Biffi A, Basso K, and Mussolin L

Subjects
Anaplastic Lymphoma Kinase, Cell Line, Tumor, Child, Gene Expression Regulation, Neoplastic, Humans, Receptor Protein-Tyrosine Kinases genetics, Transcription Factors genetics, Lymphoma, Large-Cell, Anaplastic genetics, MicroRNAs genetics
Published
2021
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49. Pre-clinical evaluation of second generation PIM inhibitors for the treatment of T-cell acute lymphoblastic leukemia and lymphoma.

Author

De Smedt R, Peirs S, Morscio J, Matthijssens F, Roels J, Reunes L, Lintermans B, Goossens S, Lammens T, Van Roy N, Touzart A, Jenni S, Tsai YC, Lovisa F, Mussolin L, Serafin V, Van Nieuwerburgh F, Deforce D, Uyttebroeck A, Tousseyn T, Burkhardt B, Klapper W, De Moerloose B, Benoit Y, Macintyre E, Bourquin JP, Basso G, Accordi B, Bornhauser B, Meijerink J, Vandenberghe P, and Van Vlierberghe P

Subjects
Cell Line, Tumor, Drug Screening Assays, Antitumor, Humans, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma enzymology, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-pim-1 antagonists & inhibitors, Proto-Oncogene Proteins c-pim-1 metabolism
Published
2019
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