{Reference Type}: Journal Article
{Title}: A case of T-cell acute lymphoblastic leukemia in retroviral gene therapy for ADA-SCID.
{Author}: Cesana D;Cicalese MP;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;
{Journal}: Nat Commun
{Volume}: 15
{Issue}: 1
{Year}: 2024 Apr 30
{Factor}: 17.694
{DOI}: 10.1038/s41467-024-47866-5
{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.