Sadat, Mohammed A.Dirscherl, SaraSastry, LakshmiDantzer, JessicaPech, NancyGriffin, SamanthaHawkins, TroyZhao, YiqiangBarese, Cecilia N.Cross, ScottOrazi, AttilioAn, CarolineGoebel, W. ScottYoder, Mervin C.Li, XiaomanGrez, ManuelCornetta, KennethMooney, Sean D.Dinauer, Mary C.2025-12-162025-12-162009Sadat MA, Dirscherl S, Sastry L, et al. Retroviral vector integration in post-transplant hematopoiesis in mice conditioned with either submyeloablative or ablative irradiation. Gene Ther. 2009;16(12):1452-1464. doi:10.1038/gt.2009.96https://hdl.handle.net/1805/52712X-linked chronic granulomatous disease (X-CGD) is an inherited immunodeficiency with absent phagocyte NADPH-oxidase activity caused by defects in the gene-encoding gp91(phox). Here, we evaluated strategies for less intensive conditioning for gene therapy of genetic blood disorders without selective advantage for gene correction, such as might be used in a human X-CGD protocol. We compared submyeloablative with ablative irradiation as conditioning in murine X-CGD, examining engraftment, oxidase activity and vector integration in mice transplanted with marrow transduced with a gamma-retroviral vector for gp91(phox) expression. The frequency of oxidase-positive neutrophils in the donor population was unexpectedly higher in many 300 cGy-conditioned mice compared with lethally irradiated recipients, as was the fraction of vector-marked donor secondary CFU-S12. Vector integration sites in marrow, spleen and secondary CFU-S12 DNA from primary recipients were enriched for cancer-associated genes, including Evi1, and integrations in or near cancer-associated genes were more frequent in marrow and secondary CFU-S12 from 300 cGy-conditioned mice compared with fully ablated mice. These findings support the concept that vector integration can confer a selection bias, and suggest that the intensity of the conditioning regimen may further influence the effects of vector integration on clonal selection in post-transplant engraftment and hematopoiesis.en-USPublisher PolicyChronic granulomatous diseaseHematopoietic stem cell transplantationNeoplasmsGenetic vectorsRetroviridaeStem cellsArticle