Fragile sites are preferential targets for integrations of MLV vectors in gene therapy.
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.
Bester
A C
AC
Department of Genetics, Silberman Life Sciences Institute, Hebrew University, Jerusalem, Israel.
Schwartz
M
M
Schmidt
M
M
Garrigue
A
A
Hacein-Bey-Abina
S
S
Cavazzana-Calvo
M
M
Ben-Porat
N
N
Von Kalle
C
C
Fischer
A
A
Kerem
B
B
D002478:Cells, Cultured; D043283:Chromosome Fragile Sites; D002873:Chromosome Fragility; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods; D005822:Genetic Vectors / Q000009:adverse effects* / Q000235:genetics; D006367:HeLa Cells / Q000821:virology; D006801:Humans; D007938:Leukemia / Q000276:immunology / Q000821:virology; D009052:Leukemia Virus, Murine / Q000235:genetics*; D016254:Mutagenesis, Insertional; D018570:Risk Assessment; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000821:virology; D016662:Virus Integration / Q000235:genetics*