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Occurrence of leukaemia following gene therapy of X-linked SCID

A Correction to this article was published on 01 November 2003

Key Points

  • Gene therapy for blood-cell diseases can be performed with retroviral vectors that insert into the genome of haematopoietic stem cells.

  • A recent trial of gene therapy for infants with X-linked severe combined immune deficiency (XSCID) successfully restored the immune systems of most subjects.

  • Two subjects developed T-cell leukaemia more than 2 years after gene therapy commenced. This cancer seems to be caused by retroviral-vector activation of a cellular oncogene at the site of integration, a process known as 'insertional oncogenesis'.

  • The complication of leukaemia has not occurred in any other clinical trial, nor in any large animal model that used retroviral vectors to modify haematopoietic stem cells. Leukaemia has been linked to vector integration in only one mouse study using this approach.

  • Multiple factors could have contributed to the development of leukaemia in the patients involved in this trial. These include the high level of engraftment and expansion of the genetically modified cells, unique properties of the haematopoietic stem and progenitor cells in bone marrow of X-linked SCID patients, the immune deficiency of the X-linked SCID patients and/or the transferred gene itself.

  • Further use of current gene-transfer methods for the treatment of SCID poses an ethical dilemma in the consideration of the complex benefits and risks.

  • It might be possible to develop retroviral vectors or other gene-therapy methods that are less likely to lead to insertional oncogenesis and still retain the therapeutic benefits. The use of tissue-specific, regulated transcription units should, in principle, diminish the risk of proto-oncogene transactivation.


Recombinant viral vectors have allowed gene transfer to be developed as a promising approach to the treatment of genetic diseases. Recently, gene therapy of children with X-linked severe combined immune deficiency resulted in impressive levels of immune reconstitution — a triumph that was later overshadowed by the development of leukaemia in two patients. What were the causes of this cancer, and how can the therapeutic benefits of gene therapy be achieved while minimizing risk to the patient?

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Figure 1: Haematopoietic stem cells and gene transfer.
Figure 2: Prevention of proto-oncogene transactivation.


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acute myeloid leukaemia




























Fanconi's anaemia



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The Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA)

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Memorial Sloan–Kettering Cancer Center

The Recombinant DNA Advisory Committee (RAC), Office of Biotechnology Assessment (OBA), the National Institutes of health (NIH)

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A DNA element that persists in the nucleus of a cell, independently of the chromosomal DNA. Episomes might be the genomes of some viruses, including herpesvirus and Epstein–Barr virus, or artifical chromosomes.


CD34 is a glycoprotein that is present on the surface of approximately 1% of human bone-marrow cells. CD34+ cells have properties of haematopoietic stem-cell and progenitor cells, in that they can proliferate and produce blood cells of various lineages. CD34+ cells can be isolated from the bone marrow or peripheral blood using commercially available immunoaffinity devices, be modified by gene transfer with retroviral vectors and be transplanted back into their donor.


A method to analyse T-cell diversity and specificity in a sample such as peripheral blood. Immunoscope analysis uses a polymerase-chain-reaction-based assay to examine the rearrangement patterns of T-cell-receptor gene families.


A cysteine- and histidine-rich, zinc-coordinating domain that is composed of two tandemly repeated zinc fingers. LIM domains do not seem to bind DNA but instead seem to mediate protein–protein interactions.


LTRs are the DNA sequences of approximately 600–800 base pairs in length that are present at both ends (5′ and 3′) of the retroviral-vector genome (provirus) — even after integration into the host-cell DNA. The U3 region of the LTR contains strong transcriptional enhancers and a promoter that drives expression of genes that are carried by most retroviral vectors. The U3 of the retroviral vector can activate expression of cellular genes that are adjacent to the site of retroviral integration.


Insulators are DNA sequences that insert between enhancer and promoter regions of DNA, blocking the ability of the enhancer to activate the promoter. Chains of genes along chromosomes can then act as isolated transcriptional units, and adjacent genes can be regulated independently. Insulators can be used to prevent a vector gene from being influenced by flanking genomic DNA sequences, or, conversely, to protect the flanking cellular genes from being influenced by the vector.

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Kohn, D., Sadelain, M. & Glorioso, J. Occurrence of leukaemia following gene therapy of X-linked SCID. Nat Rev Cancer 3, 477–488 (2003).

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