title: Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1.
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.
authors.affiliation: 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
authors.forename: Salima
authors.initials: S
authors.lastname: Hacein-Bey-Abina
authors.forename: Alexandrine
authors.initials: A
authors.lastname: Garrigue
authors.forename: Gary P
authors.initials: GP
authors.lastname: Wang
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.forename: Annick
authors.initials: A
authors.lastname: Lim
authors.forename: Estelle
authors.initials: E
authors.lastname: Morillon
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Clappier
authors.forename: Laure
authors.initials: L
authors.lastname: Caccavelli
authors.forename: Eric
authors.initials: E
authors.lastname: Delabesse
authors.forename: Kheira
authors.initials: K
authors.lastname: Beldjord
authors.forename: Vahid
authors.initials: V
authors.lastname: Asnafi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: MacIntyre
authors.forename: Liliane
authors.initials: L
authors.lastname: Dal Cortivo
authors.forename: Isabelle
authors.initials: I
authors.lastname: Radford
authors.forename: Nicole
authors.initials: N
authors.lastname: Brousse
authors.forename: François
authors.initials: F
authors.lastname: Sigaux
authors.forename: Despina
authors.initials: D
authors.lastname: Moshous
authors.forename: Julia
authors.initials: J
authors.lastname: Hauer
authors.forename: Arndt
authors.initials: A
authors.lastname: Borkhardt
authors.forename: Bernd H
authors.initials: BH
authors.lastname: Belohradsky
authors.forename: Uwe
authors.initials: U
authors.lastname: Wintergerst
authors.forename: Maria C
authors.initials: MC
authors.lastname: Velez
authors.forename: Lily
authors.initials: L
authors.lastname: Leiva
authors.forename: Ricardo
authors.initials: R
authors.lastname: Sorensen
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wulffraat
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blanche
authors.forename: Frederic D
authors.initials: FD
authors.lastname: Bushman
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana-Calvo
mesh_terms: 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*
chemical_list: 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