PAX5 fusion genes are frequent in poor risk childhood acute lymphoblastic leukaemia and can be targeted with BIBF1120
Grazia Fazio,
Silvia Bresolin,
Daniela Silvestri,
Manuel Quadri,
Claudia Saitta,
Elena Vendramini,
Barbara Buldini,
Chiara Palmi,
Michela Bardini,
Andrea Grioni,
Silvia Rigamonti,
Marta Galbiati,
Stefano Mecca,
Angela Maria Savino,
Alberto Peloso,
Jia-Wey Tu,
Sanil Bhatia,
Arndt Borkhardt,
Concetta Micalizzi,
Luca Lo Nigro,
Franco Locatelli,
Valentino Conter,
Carmelo Rizzari,
Maria Grazia Valsecchi,
Geertruij te Kronnie,
Andrea Biondi,
Giovanni Cazzaniga
Affiliations
Grazia Fazio
Centro Ricerca M. Tettamanti, Paediatrics, University of Milano Bicocca, Monza, Italy; Corresponding author at: Centro Ricerca Tettamanti, University of Milano-Bicocca, Via Pergolesi 33 - 20900 Monza (MB), Italy.
Silvia Bresolin
Paediatric Haematology, Oncology and Stem Cell Transplant Division, Women and Child Health Department, Padua University and Hospital, Padua, Italy
Daniela Silvestri
Centre of Biostatistics for Clinical Epidemiology, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
Manuel Quadri
Centro Ricerca M. Tettamanti, Paediatrics, University of Milano Bicocca, Monza, Italy
Claudia Saitta
Centro Ricerca M. Tettamanti, Paediatrics, University of Milano Bicocca, Monza, Italy
Elena Vendramini
Paediatric Haematology, Oncology and Stem Cell Transplant Division, Women and Child Health Department, Padua University and Hospital, Padua, Italy
Barbara Buldini
Paediatric Haematology, Oncology and Stem Cell Transplant Division, Women and Child Health Department, Padua University and Hospital, Padua, Italy
Chiara Palmi
Centro Ricerca M. Tettamanti, Paediatrics, University of Milano Bicocca, Monza, Italy
Michela Bardini
Centro Ricerca M. Tettamanti, Paediatrics, University of Milano Bicocca, Monza, Italy
Andrea Grioni
Centro Ricerca M. Tettamanti, Paediatrics, University of Milano Bicocca, Monza, Italy
Silvia Rigamonti
Centro Ricerca M. Tettamanti, Paediatrics, University of Milano Bicocca, Monza, Italy
Marta Galbiati
Centro Ricerca M. Tettamanti, Paediatrics, University of Milano Bicocca, Monza, Italy
Stefano Mecca
Centro Ricerca M. Tettamanti, Paediatrics, University of Milano Bicocca, Monza, Italy
Angela Maria Savino
Centro Ricerca M. Tettamanti, Paediatrics, University of Milano Bicocca, Monza, Italy; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Alberto Peloso
Paediatric Haematology, Oncology and Stem Cell Transplant Division, Women and Child Health Department, Padua University and Hospital, Padua, Italy
Jia-Wey Tu
Department of Paediatric Oncology, Haematology and Clinical Immunology, Heinrich-Heine University Dusseldorf, Medical Faculty, Düsseldorf, Germany
Sanil Bhatia
Department of Paediatric Oncology, Haematology and Clinical Immunology, Heinrich-Heine University Dusseldorf, Medical Faculty, Düsseldorf, Germany
Arndt Borkhardt
Department of Paediatric Oncology, Haematology and Clinical Immunology, Heinrich-Heine University Dusseldorf, Medical Faculty, Düsseldorf, Germany
Concetta Micalizzi
Haematology/Oncology Unit, G. Gaslini Children's Hospital, Genoa, Italy
Luca Lo Nigro
Center of Paediatric Haematology Oncology, Azienda Ospedaliero-Universitaria “Policlinico Vittorio Emanuele”, Catania, Italy
Franco Locatelli
Department of Paediatric Haematology/Oncology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Gesù, Department of Paediatrics, Sapienza University of Rome, Rome, Italy
Valentino Conter
Paediatrics, University of Milano Bicocca, Fondazione MBBM/San Gerardo Hospital, Monza, Italy
Carmelo Rizzari
Paediatrics, University of Milano Bicocca, Fondazione MBBM/San Gerardo Hospital, Monza, Italy
Maria Grazia Valsecchi
Centre of Biostatistics for Clinical Epidemiology, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
Geertruij te Kronnie
Paediatric Haematology, Oncology and Stem Cell Transplant Division, Women and Child Health Department, Padua University and Hospital, Padua, Italy
Andrea Biondi
Centro Ricerca M. Tettamanti, Paediatrics, University of Milano Bicocca, Monza, Italy; Paediatrics, University of Milano Bicocca, Fondazione MBBM/San Gerardo Hospital, Monza, Italy
Giovanni Cazzaniga
Centro Ricerca M. Tettamanti, Paediatrics, University of Milano Bicocca, Monza, Italy; Medical Genetics, University of Milano Bicocca, School of Medicine and Surgery, Monza, Italy; Corresponding author at: Centro Ricerca Tettamanti, University of Milano-Bicocca, Via Pergolesi 33 - 20900 Monza (MB), Italy.
Summary: Background: Despite intensive risk-based treatment protocols, 15% of paediatric patients with B-Cell Precursor Acute Lymphoblastic Leukaemia (BCP-ALL) experience relapse. There is urgent need of novel strategies to target poor prognosis subgroups, like PAX5 translocated. Methods: We considered 289 childhood BCP-ALL cases consecutively enrolled in Italy in the AIEOP-BFM ALL2000/R2006 protocols and we performed extensive molecular profiling, integrating gene expression, copy number analyses and fusion genes discovery by target-capture NGS. We developed preclinical strategies to target PAX5 fusion genes. Findings: We identified 135 cases without recurrent genetic rearrangements. Among them, 59 patients (43·7%) had a Ph-like signature; the remaining cases were identified as ERG-related (26%), High-Hyperdiploid-like (17%), ETV6::RUNX1-like (8·9%), MEF2D-rearranged (2·2%) or KMT2A-like (1·5%). A poor prognosis was associated with the Ph-like signature, independently from other high-risk features.Interestingly, PAX5 was altered in 54·4% of Ph-like compared to 16·2% of non-Ph-like cases, with 7 patients carrying PAX5 fusions (PAX5t), involving either novel (ALDH18A1, IKZF1, CDH13) or known (FBRSL1, AUTS2, DACH2) partner genes. PAX5t cases have a specific driver activity signature, extending to multiple pathways including LCK hyperactivation. Among FDA-approved drugs and inhibitors, we selected Dasatinib, Bosutinib and Foretinib, in addition to Nintedanib, known to be LCK ligands. We demonstrated the efficacy of the LCK-inhibitor BIBF1120/Nintedanib, as single agent or in combination with conventional chemotherapy, both ex vivo and in patient-derived xenograft model, showing a synergistic effect with dexamethasone. Interpretation: This study provides new insights in high-risk Ph-like leukaemia and identifies a potential therapy for targeting PAX5-fusion poor risk group. Funding: Ricerca Finalizzata-Giovani Ricercatori (Italian Ministry of Health), AIRC, Transcall, Fondazione Cariparo.
