RNA sequencing unravels the genetics of refractory/relapsed T-cell acute lymphoblastic leukemia. Prognostic and therapeutic implications
Valentina Gianfelici,
Sabina Chiaretti,
Sofie Demeyer,
Filomena Di Giacomo,
Monica Messina,
Roberta La Starza,
Nadia Peragine,
Francesca Paoloni,
Ellen Geerdens,
Valentina Pierini,
Loredana Elia,
Marco Mancini,
Maria Stefania De Propris,
Valerio Apicella,
Gianluca Gaidano,
Anna Maria Testi,
Antonella Vitale,
Marco Vignetti,
Cristina Mecucci,
Anna Guarini,
Jan Cools,
Robin Foà
Affiliations
Valentina Gianfelici
Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
Sabina Chiaretti
Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
Sofie Demeyer
Center for Human Genetics, KU Leuven, Belgium;Center for the Biology of Disease, VIB, Leuven, Belgium
Filomena Di Giacomo
Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy;Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Turin, Italy
Monica Messina
Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
Roberta La Starza
Hematology and Bone Marrow Transplantation Unit, Department of Medicine, University of Perugia, Italy
Nadia Peragine
Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
Francesca Paoloni
GIMEMA Data Center, Rome, Italy
Ellen Geerdens
Center for Human Genetics, KU Leuven, Belgium;Center for the Biology of Disease, VIB, Leuven, Belgium
Valentina Pierini
Hematology and Bone Marrow Transplantation Unit, Department of Medicine, University of Perugia, Italy
Loredana Elia
Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
Marco Mancini
Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
Maria Stefania De Propris
Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
Valerio Apicella
Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
Gianluca Gaidano
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Anna Maria Testi
Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
Antonella Vitale
Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
Marco Vignetti
Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy;GIMEMA Data Center, Rome, Italy
Cristina Mecucci
Hematology and Bone Marrow Transplantation Unit, Department of Medicine, University of Perugia, Italy
Anna Guarini
Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
Jan Cools
Center for Human Genetics, KU Leuven, Belgium;Center for the Biology of Disease, VIB, Leuven, Belgium
Robin Foà
Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
Despite therapeutic improvements, a sizable number of patients with T-cell acute lymphoblastic leukemia still have a poor outcome. To unravel the genomic background associated with refractoriness, we evaluated the transcriptome of 19 cases of refractory/early relapsed T-cell acute lymphoblastic leukemia (discovery cohort) by performing RNA-sequencing on diagnostic material. The incidence and prognostic impact of the most frequently mutated pathways were validated by Sanger sequencing on genomic DNA from diagnostic samples of an independent cohort of 49 cases (validation cohort), including refractory, relapsed and responsive cases. Combined gene expression and fusion transcript analyses in the discovery cohort revealed the presence of known oncogenes and identified novel rearrangements inducing overexpression, as well as inactivation of tumor suppressor genes. Mutation analysis identified JAK/STAT and RAS/PTEN as the most commonly disrupted pathways in patients with chemorefractory disease or early relapse, frequently in association with NOTCH1/FBXW7 mutations. The analysis on the validation cohort documented a significantly higher risk of relapse, inferior overall survival, disease-free survival and event-free survival in patients with JAK/STAT or RAS/PTEN alterations. Conversely, a significantly better survival was observed in patients harboring only NOTCH1/FBXW7 mutations: this favorable prognostic effect was abrogated by the presence of concomitant mutations. Preliminary in vitro assays on primary cells demonstrated sensitivity to specific inhibitors. These data document the negative prognostic impact of JAK/STAT and RAS/PTEN mutations in T-cell acute lymphoblastic leukemia and suggest the potential clinical application of JAK and PI3K/mTOR inhibitors in patients harboring mutations in these pathways.
