LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1

@article{HaceinBeyAbina2003LMO2AssociatedCT,
  title={LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1},
  author={Salima Hacein-Bey-Abina and Christof von Kalle and M. Schmidt and Matthew P. McCormack and Nico M. Wulffraat and Philippe Leboulch and Annick Lim and Cameron S Osborne and Robert Pawliuk and Estelle Morillon and Ricardo U. Sorensen and Alan Forster and P Fraser and J. I. Cohen and Genevi{\`e}ve de Saint Basile and I P Alexander and Uwe Wintergerst and Thierry Frebourg and Alain Aurias and Dominique Stoppa-Lyonnet and Serge Pierrick Romana and Isabelle Radford‐Weiss and Fabian Gross and F. Valensi and Eric Delabesse and E A Macintyre and François Sigaux and Jean Soulier and Lily E. Leiva and Manuela Wissler and Claudia Prinz and Terence H. Rabbitts and Françoise Le Deist and Alain Fischer and Marina Cavazzana‐Calvo},
  journal={Science},
  year={2003},
  volume={302},
  pages={415 - 419}
}
We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as γ chain (γc) deficiency] in 9 out of 10 patients by retrovirus-mediated γc gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with γδ+ or αβ+ T cell receptors) has occurred in the two youngest patients. Both patients' clones showed retrovirus vector integration in proximity to the… 
Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1.
TLDR
These findings functionally specify a genetic network that controls growth in T cell progenitors and led to sustained remission in 3 of the 4 cases of T cell leukemia, but failed in the fourth.
Safety Modality for X-linked Severe Combined Immunodeficiency Gene
TLDR
Proof-of-principle of a safety mechanism for SCID-X1 gene therapy that would allow elimination of gene-corrected cells in a patient upon observation of monoclonal outgrowth is shown.
Assessing the risk of T-cell malignancies in mouse models of SCID-X1.
  • B. Sorrentino
  • Biology, Medicine
    Molecular therapy : the journal of the American Society of Gene Therapy
  • 2010
TLDR
Most of the more than 30 treated patients have had full reconstitution of T-cell–mediated immunity, with restoration of B-cell function in fewer, but significant numbers of, cases, however, in both SCID-X1 trials, some patients developed T- cell malignancies that were clearly related to insertional mutagenesis from the integrated vector.
LMO2 and IL2RG synergize in thymocytes to mimic the evolution of SCID-X1 gene therapy-associated T-cell leukaemia
TLDR
Evidence is provided that synergy is required between LMO2 and IL2RG proteins specifically in the T-cell lineage to elicit neoplasias and that additional mutations are required such as Notch1 mutations like those in human T-ALL.
MDS1/EVI1 and PRDM16 deregulation in hematopoiesis after experimental and clinical gene transfer
  • Wei Wang
  • Biology
  • 2012
TLDR
This first ever large scale IDLV integration analyses yielded more than 800 unique, mappable IDLV ISs in vitro, and provided direct molecular evidence that the background integration of D64V mutant IDLVs is not mediated by residual catalytic activity of the mutant integrase.
Retroviral Insertional Mutagenesis Can Contribute to Immortalization of Mature T Lymphocytes
TLDR
It is demonstrated that insertional mutagenesis can contribute to immortalization of mature T cells, although this is a rare event, and signaling of the IL-2 receptor and the protooncogene LMO2 can act synergistically in maligniant transformation of matureT lymphocytes.
Gene Therapy for X-Linked Severe Combined Immunodeficiency: Where Do We Stand?
TLDR
The clinical experience of gene therapy for SCID-X1 is put into perspective, with the development and implementation of new generations of safer vectors such as self-inactivating gammaretroviral or lentiviral vectors as well as major advances in integrome knowledge.
Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy.
TLDR
Gene transfer into HSCs is an effective treatment for SCID, although potentially limited by the risk of insertional mutagenesis, andGene-dense regions, promoters, and transcriptionally active genes were preferred retroviral integrations sites (RISs) both in preinfusion transduced CD34(+) cells and in vivo after gene therapy.
Clonal evidence for the transduction of CD34+ cells with lymphomyeloid differentiation potential and self-renewal capacity in the SCID-X1 gene therapy trial.
TLDR
These results provide a first evidence in the setting of a clinical trial that CD34+ cells maintain both lymphomyeloid potential as well as self-renewal capacity after ex vivo manipulation.
[Gene therapy of SCID-X1].
TLDR
Activation of cellular proto-oncogenes by accidental integration of the gene vector has been identified as the underlying mechanism and improved vector technology in combination with other protocol modifications may reduce the risk of this side effect.
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