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

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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    References listed on IDEAS

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    1. Song Wu & Wei Zhu & Patricia Thompson & Yusuf A Hannun, 2018. "Evaluating intrinsic and non-intrinsic cancer risk factors," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
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