期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 118, 期 9, 页码 3132-3142出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI35700
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资金
- INSERM
- Association Francaise contre les Myopathies (AFM) [AT0203]
- Consortium National de Recherche en Genomique (CNRG)
- European Community [QLK3-CT-1999-00859, 005242, QLK3-CT-2001-00427]
- Agence Nationale de la Recherche (ANR) [05-MRAR-004]
- Canceropole Ile-de-France
- CIT ligue contre le cancer program
- Deutsche Akademie der Naturforscher Leopoldina [BMBF-LPD 9901/8-149]
- NTH [AI52845, AI66290]
- National Institute for Allergy and Infectious Diseases, NIH [T32 AI07634]
- University of Pennsylvania
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) protooncogene. 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.
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