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- Title
350. Ectopic Retroviral Expression of LMO2, but Not IL2Rγ, Blocks Human T-Cell Development from CD34+ Progenitor Cells: Implications for Gene Therapy.
- Authors
Pike-Overzet, Karin; de Ridder, Dick; Weerkamp, Floor; Baert, Miranda R. M.; Verstegen, Monique M.; Howe, Steven J.; Thrasher, Adrian J.; Wagemaker, Gerard; van Dongen, Jacques J. M.; Staal, Frank J. T.
- Abstract
The occurrence of leukemia in 3 out of 11 patients in a gene therapy trial for SCID-X1 emphasized insertional mutagenesis as an adverse effect. In two out of three patients retroviral integration occurred near the T-cell acute lymphoblastic leukemia (T-ALL) oncogene LIM-only protein 2 (LMO2). It has remained unclear why LMO2 was preferentially targeted. We show here that of classical T-ALL oncogenes, mainly LMO2 is transcribed in CD34+ progenitor cells derived from umbilical cord blood (UCB). Upon stimulation with growth factors typically used in gene therapy protocols, transcription of LMO2, LYL1 and TAL1 increased 2–3 fold in CD34+ UCB cells, whereas the other T-ALL oncogenes remained unaffected. Similarly, when mobilized peripheral blood CD34+ cells were stimulated according to transduction protocols used for clinical SCID-X1 gene therapy trials, the same pattern of T-ALL oncogene transcription was observed, suggesting that cytokine stimulation leads to upregulation of proto-oncogenes irrespective of the source of CD34+ progenitor cells used. Transcription of LMO2, LYL1 and TAL1 is particularly high and their loci could therefore be preferentially accessible for viral integration. Retroviral overexpression of LMO2 in CD34+ cells led to severe abnormalities in human T-cell development, but B-cell, NK cell and myeloid development remained unaffected. The interleukin-2 receptor gamma chain (IL2Rγ), causing SCID-X1 when mutated, has been proposed to act as an oncogene cooperative to LMO2. However, we found that overexpression of IL2Rγ had no effect on T-cell development. Moreover, IL2Rγ normally is expressed at high levels in CD34+ progenitor cells and at even higher levels in the thymus. Thus, transduction of IL2Rγ in CD34+ progenitor cells does not cause ectopic expression of this gene. In conclusion, our data provide an explanation why LMO2 was preferentially targeted over other known T-ALL oncogenes. Furthermore, IL2Rγ does not appear to act as an oncogene. Rather, the normal IL2Rγ chain restores IL7 receptor signalling in the progeny of transduced SCID-X1 cells developing in the thymus, allowing T-cell development to progress to stages where ectopic LMO2 expression hampers T-cell development in the thymus, creating a probable pre-leukemic condition by accumulation of immature cells under intense proliferative pressure.Molecular Therapy (2006) 13, S133–S133; doi: 10.1016/j.ymthe.2006.08.408
- Subjects
LEUKEMIA; GENE therapy; MUTAGENESIS; LYMPHOBLASTIC leukemia; GENETIC transcription; GENETIC transduction
- Publication
Molecular Therapy, 2006, Vol 13, pS133
- ISSN
1525-0016
- Publication type
Article
- DOI
10.1016/j.ymthe.2006.08.408