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Gene expression signature for early prediction of late occurring pancytopenia in irradiated baboons.

ABSTRACT: Based on gene expression changes measured in the peripheral blood within the first 2 days after irradiation, we predicted a pancytopenia in a baboon model. Eighteen baboons were irradiated with 2.5 or 5 Gy. According to changes in blood cell counts, the surviving baboons (n = 17) exhibited a hematological acute radiation syndrome (HARS) either with or without a pancytopenia. We used a two stage study design where stage I was a whole genome screen (microarrays) for mRNA combined with a qRT-PCR platform for simultaneous detection of 667 miRNAs using a part of the samples. Candidate mRNAs and miRNAs differentially upregulated or downregulated (>2-fold, p < 0.05) during the first 2 days after irradiation were chosen for validation in stage II using the remaining samples and using throughout more sensitive qRT-PCR. We detected about twice as many upregulated (mean 2128) than downregulated genes (mean 789) in baboons developing an HARS either with or without a pancytopenia. From 51 candidate mRNAs altogether, 11 mRNAs were validated using qRT-PCR. These mRNAs showed only significant differences between HARS groups and H0, but not between HARS groups with and without pancytopenia. Six miRNA species (e.g., miR-574-3p, p = 0.009, ROC = 0.94) revealed significant gene expression differences between HARS groups with and without pancytopenia and are known to sensitize irradiated cells. Hence, in particular, the newly identified miRNA species for prediction of pancytopenia will support the medical management decision making.

SUBMITTER: Port M

PROVIDER: S-EPMC5371629 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Gene expression signature for early prediction of late occurring pancytopenia in irradiated baboons.

Port Matthias M Hérodin Francis F Valente Marco M Drouet Michel M Lamkowski Andreas A Majewski Matthäus M Abend Michael M

Annals of hematology 20170224 5

Based on gene expression changes measured in the peripheral blood within the first 2 days after irradiation, we predicted a pancytopenia in a baboon model. Eighteen baboons were irradiated with 2.5 or 5 Gy. According to changes in blood cell counts, the surviving baboons (n = 17) exhibited a hematological acute radiation syndrome (HARS) either with or without a pancytopenia. We used a two stage study design where stage I was a whole genome screen (microarrays) for mRNA combined with a qRT-PCR pl ...[more]

PMID: 28236054

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Project description:Based on gene expression changes measured in the peripheral blood within the first 2 days after irradiation we aimed to predict the later occurring hematological acute radiation syndrome (HARS). Altogether 18 baboons were irradiated simulating different patterns of partial body irradiation or total body irradiation corresponding to an equivalent dose of 2.5 or 5 Gy. According to changes in blood cell counts (BCC) they were either suffering from H1-2 (n=4) or H2-3 (n=13) degree HARS. One animal was deleted from analysis due to unusual changes in BCC and early death. Blood samples taken before irradiation served as H0 (n=17). A two stage study design was applied. During first stage we screened the whole genome (mRNA microarrays) using one part of the samples (H0 n=5, H1-2 n=4, H2-3 n=5). Candidate genes differentially up- or down-regulated during the first two days after irradiation were forwarded for validation in stage II using the remaining samples and changing the methodology (qRT-PCR). Differential gene expression was defined as a significant (p<0.05) and > 2-fold difference in gene expression over H0. From about 20,000 genes on average 46% appeared expressed. At H2-3 and day 1 about 2-3 times more genes appeared up-regulated (1,418 versus 550) or down-regulated (1,603 versus 735) compared to H1-2 an effect which became pronounced at day 2 while the number of differentially expressed genes decreased. These genes did show an enrichment regarding biological processes coding for immune system processes, natural killer cell activation and immune response (p= 1xE-06 up to 9xE-14). Based on the p-value, the height and constant differential gene expression over time, 89 candidate genes were selected for validation using qRT-PCR. Finally, 22 genes for identification of H1-3 and 7 genes for identification of H2-3 were confirmed using qRT-PCR. For H1-3 most genes were constantly and 3-5 fold down-regulated relative to H0 over both days, but some genes appeared 10.3-fold (VSIG4) or even 30.7-fold up-regulated (CD177) over H0. For H2-3 some genes appeared 4-7-fold up-regulated relative to H0 (RNASE3, DAGLA, ARG2), but other genes showed a strong and 14-33-fold down-regulation relative to H0 (WNT3, POU2AF1, CCR7). Each of the genes allowed an almost complete separation of HARS categories. Taken together, clinical relevant HARS can be independently predicted with each of 29 radiation-induced genes examined in the peripheral blood of baboons within the first two days after irradiation.

Dataset Information

Gene expression signature for early prediction of late occurring pancytopenia in irradiated baboons.

Publications

Gene expression signature for early prediction of late occurring pancytopenia in irradiated baboons.

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