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The impact of the Trp53 allelic state on the response to gamma-irradiation in hematopoietic stem and progenitor cells

ABSTRACT: We investigated how the Trp53 allelic state influences the response of hematopoietic stem and progenitor cells (HSPCs) to γ-irradiation. We used a transgenic mouse model harboring hematopoietic cell–specific, tamoxifen-inducible Trp53-R245W missense mutations linked to a GFP reporter. In mice with biallelic transgenes, tamoxifen treatment generates three GFP-defined populations: GFP-negative cells (Trp53 wild-type), GFP-low cells (monoallelic Trp53 mutation, due to recombination of only one transgenic allele), and GFP-high cells (biallelic Trp53 mutation). Flow sorting of these populations enables direct comparison of all three allelic states in HSPCs. Using this system, we sought to define the transcriptional responses of HSPCs with different Trp53 genotypes following γ-irradiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE306213 | GEO | 2025/08/26

REPOSITORIES: GEO

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Project description:The occurrence of clonal perturbations and leukemia in patients transplanted with retrovirally-transduced autologous hematopoietic stem and progenitor cells (HSPCs) has stimulated extensive investigation, demonstrating that proviral insertions perturb adjacent proto-oncogene expression. Although enhancer-deleted lentiviruses are less likely to result in insertional oncogenesis, there is evidence that they may perturb transcript splicing, and one patient with a benign clonal expansion of lentivirally-transduced HPSC has been reported. The rhesus macaque model provides an opportunity for informative long-term analysis to ask whether transduction impacts on long-term HSPC properties. We utilized two techniques to examine whether lentivirally-transduced HSPCs from eight rhesus macaques transplanted 1-13.5 years previously are perturbed at a population level, comparing telomere length as a measure of replicative history and gene expression profile of vector positive versus vector negative cells. There were no differences in telomere lengths between sorted GFP+ and GFP- blood cells, suggesting that lentiviral transduction did not globally disrupt replicative patterns. Bone marrow GFP+ and GFP- CD34+ cells showed no differences in gene expression using unsupervised and principal component analysis. These studies did not uncover any global long-term perturbation of proliferation, differentiation, or other important functional parameters of transduced HSPCs in the rhesus macaque model. CD34+ hematopoietic stem and progenitor cells were purified from bone marrow aspirates obtained from 4 rhesus macaques 3-9 years following transplantation with lentivirally-transduced autologous hematopoietic stem and progenitor cells. All lentiviral vectors contained the GFP marker gene. The CD34+ cells from each animal were sorted via flow cytometry into GFP+ and GFP- fractions, and RNA from these cells was used for Affymetrix gene expression analysis as detailed below. There were two samples, GFP+ and GFP-, from each of 4 animals.

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The impact of the Trp53 allelic state on the response to gamma-irradiation in hematopoietic stem and progenitor cells

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