Fragile sites are preferential targets for integrations of MLV vectors in gene therapy

@article{Bester2006FragileSA,
  title={Fragile sites are preferential targets for integrations of MLV vectors in gene therapy},
  author={Assaf Chanan Bester and Michal Schwartz and M. Schmidt and Alexandrine Garrigue and Salima Hacein-Bey-Abina and Marina Cavazzana‐Calvo and Neta Ben-Porat and Christof von Kalle and A Fischer and Batsheva Kerem},
  journal={Gene Therapy},
  year={2006},
  volume={13},
  pages={1057-1059}
}
Following gene therapy of SCID-X1 using murine leukemia virus (MLV) derived vector, two patients developed leukemia owing to an activating vector integration near the LMO2 gene. We found that these integrations reside within FRA11E, a common fragile site known to correlate with chromosomal breakpoints in tumors. Further analysis showed that fragile sites attract a nonrandom number of MLV integrations, shedding light on its integration mechanism and risk-to-benefit ratio in gene therapy. 

Infection with retroviral vectors leads to perturbed DNA replication increasing vector integrations into fragile sites

The genomic region of FRA11H harbors a hotspot of chromosomal breakpoints found in different types of cancer, indicating that this region is unstable during cancer development, and suggests that infection by MLV-based vectors leads to replication-induced genome instability, raising further concerns regarding the use of retroviral vectors in gene therapy trials.

Development of Safer Gene Delivery Systems to Minimize the Risk of Insertional Mutagenesis-Related Malignancies: A Critical Issue for the Field of Gene Therapy

The latest achievements that have been reported in the field of vector design are discussed, including adeno-associated-viral-(AAV-) mediated gene transfer induced tumors in animal models, whereas the Sleeping Beauty DNA transposon system was associated with insertional mutagenesis events in cell culture systems.

Transduction of fetal mice with a feline lentiviral vector induces liver tumors which exhibit an E2F activation signature.

It is proposed that transduction of fetal mice with a feline lentiviral vector induces E2F-mediated major cellular processes that drive hepatocytes toward uncontrolled proliferation culminating in tumorigenesis.

Retroviral Integrations in Gene Therapy Trials

This review is aimed at critically revising the data derived from insertional profiling, with a particular focus on the evidences collected from GT clinical trials, to address broader biological questions, from basic virology to human hematopoiesis.

Role of SV40 integration site at chromosomal interval 1q21.1 in immortalized CRL2504 cells.

The results suggest that the disruption of native genomic sequence by SV40 may alter expression of genes involved in senescence and apoptosis by modulating chromatin structure, and imply that identification of genes located in the vicinity of viral integration sites in human cancers may be helpful in developing new diagnostic and therapeutic strategies.

Novel aphidicolin‐inducible common fragile site FRA9G maps to 9p22.2, within the C9orf39 gene

Analysis of incidence in healthy individuals showed that FRA9G is commonly expressed in the population, and characterized the structure of the fragile DNA sequence that extends over a genomic region of ∼300 kb within the C9orf39 (chromosome 9 open reading frame 39) gene.

Cloning of genetically tagged chromosome break sequences reveals new fragile sites at 6p21 and 13q22

Fragile sites are specific genomic loci that are especially prone to chromosome breakage. For the human genome there are 31 rare fragile sites and 88 common fragile sites listed in the National

Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy.

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.

Integration Site Preference of Xenotropic Murine Leukemia Virus-Related Virus, a New Human Retrovirus Associated with Prostate Cancer

In both acutely infected cells and cancer tissues, no common integration site was detected within or near proto-oncogenes or tumor suppressor genes, consistent with a model in which XMRV may contribute to tumorigenicity via a paracrine mechanism.

Impaired Replication Timing Promotes Tissue-Specific Expression of Common Fragile Sites

The induction of two CFSs previously found in the human fetal lung fibroblast line are validated in another cell line derived from the same fetal tissue, Institute for Medical Research-90 cells (IMR-90) and the expression of the CFS 1p31.1 and 3q13.3 sites were found to not be fragile in lymphocytes, suggesting a role for epigenetic or transcriptional programs for this tissue specificity.

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