%0 Journal Article
%T A case of T-cell acute lymphoblastic leukemia in retroviral gene therapy for ADA-SCID.
%A Cesana D
%A Cicalese MP
%A Calabria A
%A Merli P
%A Caruso R
%A Volpin M
%A Rudilosso L
%A Migliavacca M
%A Barzaghi F
%A Fossati C
%A Gazzo F
%A Pizzi S
%A Ciolfi A
%A Bruselles A
%A Tucci F
%A Spinozzi G
%A Pais G
%A Benedicenti F
%A Barcella M
%A Merelli I
%A Gallina P
%A Giannelli S
%A Dionisio F
%A Scala S
%A Casiraghi M
%A Strocchio L
%A Vinti L
%A Pacillo L
%A Draghi E
%A Cesana M
%A Riccardo S
%A Colantuono C
%A Six E
%A Cavazzana M
%A Carlucci F
%A Schmidt M
%A Cancrini C
%A Ciceri F
%A Vago L
%A Cacchiarelli D
%A Gentner B
%A Naldini L
%A Tartaglia M
%A Montini E
%A Locatelli F
%A Aiuti A
%J Nat Commun
%V 15
%N 1
%D 2024 Apr 30
%M 38688902
%F 17.694
%R 10.1038/s41467-024-47866-5
%X 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.