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, D.; Cicalese, M. P.; Calabria, A.; Merli, P.; Caruso, R.; Volpin, M.; Rudilosso, L.; Migliavacca, M.; Barzaghi, F.; Fossati, C.; Gazzo, F.; Pizzi, S.; Ciolfi, A.; Bruselles, A.; Tucci, F.; Spinozzi, G.; Pais, G.; Benedicenti, F.; Barcella, M.; Merelli, I.; Gallina, P.; Giannelli, S.; Dionisio, F.; Scala, S.; Casiraghi, M.; Strocchio, L.; Vinti, L.; Pacillo, L.; Draghi, E.; Cesana, M.; Riccardo, S.; Colantuono, C.; Six, E.; Cavazzana, M.; Carlucci, F.; Schmidt, M.; Cancrini, C.; Ciceri, F.; Vago, L.; Cacchiarelli, D.; Gentner, B.; Naldini, L.; Tartaglia, M.; Montini, E.; Locatelli, F.; Aiuti, A.. - 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 M. P.;Draghi E.;Ciceri F.;Vago L.;Naldini L.;Aiuti A.
2024-01-01
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.
