: Hematopoietic stem cell gene therapy (GT) using a γ-retroviral vector (γ-RV) is an effective treatment for Severe Combined Immunodeficiency due to Adenosine Deaminase deficiency. Here, we describe a case of GT-related T-cell acute lymphoblastic leukemia (T-ALL) that developed 4.7 years after treatment. The patient underwent chemotherapy and haploidentical transplantation and is currently in remission. Blast cells contain a single vector insertion activating the LIM-only protein 2 (LMO2) proto-oncogene, confirmed by physical interaction, and low Adenosine Deaminase (ADA) activity resulting from methylation of viral promoter. The insertion is detected years before T-ALL in multiple lineages, suggesting that further hits occurred in a thymic progenitor. Blast cells contain known and novel somatic mutations as well as germline mutations which may have contributed to transformation. Before T-ALL onset, the insertion profile is similar to those of other ADA-deficient patients. The limited incidence of vector-related adverse events in ADA-deficiency compared to other γ-RV GT trials could be explained by differences in transgenes, background disease and patient's specific factors.
A case of T-cell acute lymphoblastic leukemia in retroviral gene therapy for ADA-SCID / Cesana, Daniela; Cicalese, Maria Pia; Calabria, Andrea; Merli, Pietro; Caruso, Roberta; Volpin, Monica; Rudilosso, Laura; Migliavacca, Maddalena; Barzaghi, Federica; Fossati, Claudia; Gazzo, Francesco; Pizzi, Simone; Ciolfi, Andrea; Bruselles, Alessandro; Tucci, Francesca; Spinozzi, Giulio; Pais, Giulia; Benedicenti, Fabrizio; Barcella, Matteo; Merelli, Ivan; Gallina, Pierangela; Giannelli, Stefania; Dionisio, Francesca; Scala, Serena; Casiraghi, Miriam; Strocchio, Luisa; Vinti, Luciana; Pacillo, Lucia; Draghi, Eleonora; Cesana, Marcella; Riccardo, Sara; Colantuono, Chiara; Six, Emmanuelle; Cavazzana, Marina; Carlucci, Filippo; Schmidt, Manfred; Cancrini, Caterina; Ciceri, Fabio; Vago, Luca; Cacchiarelli, Davide; Gentner, Bernhard; Naldini, Luigi; Tartaglia, Marco; Montini, Eugenio; Locatelli, Franco; Aiuti, Alessandro. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 15:1(2024). [10.1038/s41467-024-47866-5]
A case of T-cell acute lymphoblastic leukemia in retroviral gene therapy for ADA-SCID
Cicalese, Maria Pia;Merli, Pietro;Caruso, Roberta;Tucci, Francesca;Cesana, Marcella;Colantuono, Chiara;Cacchiarelli, Davide;Locatelli, Franco;
2024
Abstract
: Hematopoietic stem cell gene therapy (GT) using a γ-retroviral vector (γ-RV) is an effective treatment for Severe Combined Immunodeficiency due to Adenosine Deaminase deficiency. Here, we describe a case of GT-related T-cell acute lymphoblastic leukemia (T-ALL) that developed 4.7 years after treatment. The patient underwent chemotherapy and haploidentical transplantation and is currently in remission. Blast cells contain a single vector insertion activating the LIM-only protein 2 (LMO2) proto-oncogene, confirmed by physical interaction, and low Adenosine Deaminase (ADA) activity resulting from methylation of viral promoter. The insertion is detected years before T-ALL in multiple lineages, suggesting that further hits occurred in a thymic progenitor. Blast cells contain known and novel somatic mutations as well as germline mutations which may have contributed to transformation. Before T-ALL onset, the insertion profile is similar to those of other ADA-deficient patients. The limited incidence of vector-related adverse events in ADA-deficiency compared to other γ-RV GT trials could be explained by differences in transgenes, background disease and patient's specific factors.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.