Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1.
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.
Hacein-Bey-Abina
Salima
S
Department of Biotherapy, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université René Descartes, Paris, France. salima.hacein-bey@nck.ap-hop-paris.fr
Garrigue
Alexandrine
A
Wang
Gary P
GP
Soulier
Jean
J
Lim
Annick
A
Morillon
Estelle
E
Clappier
Emmanuelle
E
Caccavelli
Laure
L
Delabesse
Eric
E
Beldjord
Kheira
K
Asnafi
Vahid
V
MacIntyre
Elizabeth
E
Dal Cortivo
Liliane
L
Radford
Isabelle
I
Brousse
Nicole
N
Sigaux
François
F
Moshous
Despina
D
Hauer
Julia
J
Borkhardt
Arndt
A
Belohradsky
Bernd H
BH
Wintergerst
Uwe
U
Velez
Maria C
MC
Leiva
Lily
L
Sorensen
Ricardo
R
Wulffraat
Nicolas
N
Blanche
Stéphane
S
Bushman
Frederic D
FD
Fischer
Alain
A
Cavazzana-Calvo
Marina
M
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000494:pharmacology; D002869:Chromosome Aberrations; D041321:Chromosomes, Human, X; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D017988:Gammaretrovirus / Q000378:metabolism; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods*; D006801:Humans; D007223:Infant; D053616:Janus Kinase 3 / Q000235:genetics; D060588:LIM Domain Proteins; D015458:Leukemia, T-Cell / Q000150:complications / Q000209:etiology* / Q000628:therapy; D008667:Metalloproteins / Q000235:genetics; D008954:Models, Biological; D009154:Mutation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D015375:Receptors, Interleukin-2 / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000150:complications / Q000628:therapy*
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; C000715470:MAS1 protein, human; D008667:Metalloproteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D015375:Receptors, Interleukin-2; C507933:JAK3 protein, human; D053616:Janus Kinase 3