A case of T-cell acute lymphoblastic leukemia in retroviral gene therapy for ADA-SCID

Nat Commun. 2024 Apr 30;15(1):3662. 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Case Reports

MeSH terms

  • Adenosine Deaminase* / deficiency
  • Adenosine Deaminase* / genetics
  • Agammaglobulinemia* / genetics
  • Agammaglobulinemia* / therapy
  • Genetic Therapy* / methods
  • Genetic Vectors* / genetics
  • Hematopoietic Stem Cell Transplantation*
  • Humans
  • Male
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / therapy
  • Proto-Oncogene Mas*
  • Retroviridae / genetics
  • Severe Combined Immunodeficiency* / genetics
  • Severe Combined Immunodeficiency* / therapy

Substances

  • Adenosine Deaminase
  • Proto-Oncogene Mas
  • MAS1 protein, human

Supplementary concepts

  • Severe combined immunodeficiency due to adenosine deaminase deficiency