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- Title
Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1.
- Authors
Hacein-Bey-Abina, Salima; Garrigue, Alexandrine; Wang, Gary P.; Soulier, Jean; Lim, Annick; Morillon, Estelle; Clappier, Emmanuelle; Caccavelli, Laure; Delabesse, Eric; Beldjord, Kheira; Asnafi, Vahid; MacIntyre, Elizabeth; Dal Cortivo, Liliane; Radford, Isabelle; Brousse, Nicole; Sigaux, François; Moshous, Despina; Hauer, Julia; Borkhardt, Arndt; Belohradsky, Bernd H.
- Abstract
Previously, several individuals with X-linked SCID (SCID-X1) were treated by gene therapy to restore the missing IL-2 receptor gamma (IL2RG) gene to CD34+ BM precursor cells using gammaretroviral vectors. While 9 of 10 patients were successfully treated, 4 of the 9 developed T cell leukemia 31-68 months after gene therapy. In 2 of these cases, blast cells contained activating vector insertions near the LIM domain-only 2 (LMO2) proto-oncogene. Here, we report data on the 2 most recent adverse events, which occurred in patients 7 and 10. In patient 10, blast cells contained an integrated vector near LMO2 and a second integrated vector near the proto-oncogene BMI1. In patient 7, blast cells contained an integrated vector near a third proto-oncogene,CCND2. Additional genetic abnormalities in the patients' blast cells included chromosomal translocations, gain-of-function mutations activating NOTCH1, and copy number changes, including deletion of tumor suppressor gene CDKN2A, 6q interstitial losses, and SIL-TAL1 rearrangement. These findings functionally specify a genetic network that controls growth in T cell progenitors. Chemotherapy led to sustained remission in 3 of the 4 cases of T cell leukemia, but failed in the fourth. Successful chemotherapy was associated with restoration of polyclonal transduced T cell populations. As a result, the treated patients continued to benefit from therapeutic gene transfer.
- Subjects
BIOTHERAPY; GENE therapy; ONCOGENES; T cells; LEUKEMIA; GENETIC transformation; ANTINEOPLASTIC agents; BIOLOGICAL models; CARRIER proteins; CELL receptors; CHROMOSOME abnormalities; CHROMOSOMES; CLINICAL trials; COMPARATIVE studies; LYMPHOCYTIC leukemia; RESEARCH methodology; MEDICAL cooperation; METALLOPROTEINS; GENETIC mutation; PROTEINS; RESEARCH; RESEARCH funding; RETROVIRUSES; DNA-binding proteins; EVALUATION research; DISEASE complications; SEVERE combined immunodeficiency; PHARMACODYNAMICS; THERAPEUTICS; LEUKEMIA treatment
- Publication
Journal of Clinical Investigation, 2008, Vol 118, Issue 9, p3132
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI35700