Previously, several individuals with X-linked SCID (SCID-X1) were treated by gene therapy to restore the missing IL-2 receptor γ (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.


Salima Hacein-Bey-Abina, Alexandrine Garrigue, Gary P. Wang, Jean Soulier, Annick Lim, Estelle Morillon, Emmanuelle Clappier, Laure Caccavelli, Eric Delabesse, Kheira Beldjord, Vahid Asnafi, Elizabeth MacIntyre, Liliane Dal Cortivo, Isabelle Radford, Nicole Brousse, François Sigaux, Despina Moshous, Julia Hauer, Arndt Borkhardt, Bernd H. Belohradsky, Uwe Wintergerst, Maria C. Velez, Lily Leiva, Ricardo Sorensen, Nicolas Wulffraat, Stéphane Blanche, Frederic D. Bushman, Alain Fischer, Marina Cavazzana-Calvo


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