Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1
Salima Hacein-Bey-Abina, … , Alain Fischer, Marina Cavazzana-Calvo
Salima Hacein-Bey-Abina, … , Alain Fischer, Marina Cavazzana-Calvo
Published August 7, 2008
Citation Information: J Clin Invest. 2008;118(9):3132-3142. https://doi.org/10.1172/JCI35700.
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Research Article

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 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.

Authors

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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Figure 5

Expression of proto-oncogenes.

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Expression of proto-oncogenes. (A) CCND2 expression analysis in P7 blast...
(A) CCND2 expression analysis in P7 blast cells compared with a series of primary T-ALL cases from different oncogenic subgroups — CCND2-rearranged cases (TCR-CCND2; n = 3) and other T-ALL primary cases (T-ALL; n = 86) — and with normal thymus (n = 3). CCND2 expression levels are shown as copy number value in a given sample related to TBP copy number in the series, as determined using the ΔCt method. CCND2 levels in 11 normal human thymic subpopulations were previously analyzed for comparison and showed varied gene expression depending on the cells’ stage of thymic differentiation (18). Results are presented as a box plot: the box boundaries indicates the twenty-fifth and seventy-fifth percentiles; the line within the box denotes the median; whiskers denote tenth and ninetieth percentiles; outliers are indicated as dots. (B) RQ-PCR of SPAG6, BMI1, COMMD3, and DNAJC1 genes in P10 leukemic sample at M+33 compared with CALM-AF10–positive (CA+; n = 14) and –negative (CA–; n = 31) samples. The ratio of gene expression relative to ABL was calculated for each sample. Below, the genomic organization around the AF10 breakpoint is presented along with the location of the γc retrovirus insertion. (C) Longitudinal expression of LMO2 in P10 as determined by RQ-PCR.