Author
Listed:
- Daniela Cesana
(IRCCS San Raffaele Scientific Institute)
- Maria Pia Cicalese
(IRCCS San Raffaele Scientific Institute
IRCCS San Raffaele Scientific Institute
Università Vita-Salute San Raffaele)
- Andrea Calabria
(IRCCS San Raffaele Scientific Institute)
- Pietro Merli
(IRCCS Bambino Gesù Children’s Hospital)
- Roberta Caruso
(IRCCS Bambino Gesù Children’s Hospital)
- Monica Volpin
(IRCCS San Raffaele Scientific Institute)
- Laura Rudilosso
(IRCCS San Raffaele Scientific Institute)
- Maddalena Migliavacca
(IRCCS San Raffaele Scientific Institute
IRCCS San Raffaele Scientific Institute)
- Federica Barzaghi
(IRCCS San Raffaele Scientific Institute
IRCCS San Raffaele Scientific Institute)
- Claudia Fossati
(IRCCS San Raffaele Scientific Institute)
- Francesco Gazzo
(IRCCS San Raffaele Scientific Institute)
- Simone Pizzi
(IRCCS Bambino Gesù Children’s Hospital)
- Andrea Ciolfi
(IRCCS Bambino Gesù Children’s Hospital)
- Alessandro Bruselles
(Istituto Superiore di Sanità)
- Francesca Tucci
(IRCCS San Raffaele Scientific Institute
IRCCS San Raffaele Scientific Institute)
- Giulio Spinozzi
(IRCCS San Raffaele Scientific Institute)
- Giulia Pais
(IRCCS San Raffaele Scientific Institute)
- Fabrizio Benedicenti
(IRCCS San Raffaele Scientific Institute)
- Matteo Barcella
(IRCCS San Raffaele Scientific Institute
Institute for Biomedical Technologies)
- Ivan Merelli
(IRCCS San Raffaele Scientific Institute
Institute for Biomedical Technologies)
- Pierangela Gallina
(IRCCS San Raffaele Scientific Institute)
- Stefania Giannelli
(IRCCS San Raffaele Scientific Institute)
- Francesca Dionisio
(IRCCS San Raffaele Scientific Institute)
- Serena Scala
(IRCCS San Raffaele Scientific Institute)
- Miriam Casiraghi
(IRCCS San Raffaele Scientific Institute)
- Luisa Strocchio
(IRCCS Bambino Gesù Children’s Hospital)
- Luciana Vinti
(IRCCS Bambino Gesù Children’s Hospital)
- Lucia Pacillo
(IRCCS Bambino Gesù Children’s Hospital)
- Eleonora Draghi
(Ospedale San Raffaele Scientific Institute)
- Marcella Cesana
(Armenise/Harvard Laboratory of Integrative Genomics
University of Naples “Federico II”)
- Sara Riccardo
(Armenise/Harvard Laboratory of Integrative Genomics
NEGEDIA S.r.l.)
- Chiara Colantuono
(Armenise/Harvard Laboratory of Integrative Genomics
NEGEDIA S.r.l.)
- Emmanuelle Six
(INSERM)
- Marina Cavazzana
(INSERM)
- Filippo Carlucci
(University of Siena)
- Manfred Schmidt
(Genewerk GmbH)
- Caterina Cancrini
(IRCCS Bambino Gesù Children’s Hospital
Department of Systems Medicine University of Rome Tor Vergata)
- Fabio Ciceri
(IRCCS San Raffaele Scientific Institute
Università Vita-Salute San Raffaele
San Raffaele Scientific Institute)
- Luca Vago
(Università Vita-Salute San Raffaele
Ospedale San Raffaele Scientific Institute
San Raffaele Scientific Institute)
- Davide Cacchiarelli
(Armenise/Harvard Laboratory of Integrative Genomics
University of Naples “Federico II”
University of Naples “Federico II”)
- Bernhard Gentner
(IRCCS San Raffaele Scientific Institute
San Raffaele Scientific Institute)
- Luigi Naldini
(IRCCS San Raffaele Scientific Institute
Università Vita-Salute San Raffaele)
- Marco Tartaglia
(IRCCS Bambino Gesù Children’s Hospital)
- Eugenio Montini
(IRCCS San Raffaele Scientific Institute)
- Franco Locatelli
(IRCCS Ospedale Pediatrico Bambino Gesù
Università Cattolica del Sacro Cuore)
- Alessandro Aiuti
(IRCCS San Raffaele Scientific Institute
IRCCS San Raffaele Scientific Institute
Università Vita-Salute San Raffaele)
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.
Suggested Citation
Daniela Cesana & Maria Pia Cicalese & Andrea Calabria & Pietro Merli & Roberta Caruso & Monica Volpin & Laura Rudilosso & Maddalena Migliavacca & Federica Barzaghi & Claudia Fossati & Francesco Gazzo , 2024.
"A case of T-cell acute lymphoblastic leukemia in retroviral gene therapy for ADA-SCID,"
Nature Communications, Nature, vol. 15(1), pages 1-18, December.
Handle:
RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47866-5
DOI: 10.1038/s41467-024-47866-5
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