A case of T-cell acute lymphoblastic leukemia in retroviral gene therapy for ADA-SCID.
Humans
Adenosine Deaminase
/ deficiency
Genetic Therapy
/ methods
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
/ therapy
Proto-Oncogene Mas
Severe Combined Immunodeficiency
/ therapy
Genetic Vectors
/ genetics
Hematopoietic Stem Cell Transplantation
Agammaglobulinemia
/ therapy
Male
Retroviridae
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
30 Apr 2024
30 Apr 2024
Historique:
received:
13
10
2023
accepted:
10
04
2024
medline:
1
5
2024
pubmed:
1
5
2024
entrez:
30
4
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38688902
doi: 10.1038/s41467-024-47866-5
pii: 10.1038/s41467-024-47866-5
doi:
Substances chimiques
Adenosine Deaminase
EC 3.5.4.4
Proto-Oncogene Mas
0
MAS1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Case Reports
Langues
eng
Sous-ensembles de citation
IM
Pagination
3662Subventions
Organisme : Ministry of Health, Italy | Agenzia Italiana del Farmaco, Ministero della Salute (Italian Medicines Agency)
ID : GR-2018-12367860
Organisme : Fondazione Italiana per la Ricerca sul Cancro (Italian Foundation for Cancer Research)
ID : IG #22197
Organisme : Fondazione Italiana per la Ricerca sul Cancro (Italian Foundation for Cancer Research)
ID : 9962
Organisme : Fondazione Italiana per la Ricerca sul Cancro (Italian Foundation for Cancer Research)
ID : IG #21614
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)
ID : PRIN 2017WC8499_004
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)
ID : FOE 2019
Informations de copyright
© 2024. The Author(s).
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