title: 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.
authors.affiliation: Bundeswehr Institute of Radiobiology affiliated to the University of Ulm, Neuherbergstr. 11, 80937, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Port
authors.affiliation: Institut de Recherche Biomedicale des Armees, Bretigny-sur-Orge, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Hérodin
authors.affiliation: Institut de Recherche Biomedicale des Armees, Bretigny-sur-Orge, France.
authors.forename: Marco
authors.initials: M
authors.lastname: Valente
authors.affiliation: Institut de Recherche Biomedicale des Armees, Bretigny-sur-Orge, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Drouet
authors.affiliation: Bundeswehr Institute of Radiobiology affiliated to the University of Ulm, Neuherbergstr. 11, 80937, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lamkowski
authors.affiliation: Bundeswehr Institute of Radiobiology affiliated to the University of Ulm, Neuherbergstr. 11, 80937, Munich, Germany.
authors.forename: Matthäus
authors.initials: M
authors.lastname: Majewski
authors.affiliation: Bundeswehr Institute of Radiobiology affiliated to the University of Ulm, Neuherbergstr. 11, 80937, Munich, Germany. michaelabend@bundeswehr.org.
authors.forename: Michael
authors.initials: M
authors.lastname: Abend
mesh_terms: D000818:Animals; D001772:Blood Cell Count; D019295:Computational Biology / Q000379:methods; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D023281:Genomics / Q000379:methods; D017619:Hemibody Irradiation; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D010198:Pancytopenia / Q000097:blood / Q000175:diagnosis* / Q000209:etiology*; D010215:Papio; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D015203:Reproducibility of Results; D012720:Severity of Illness Index; D059467:Transcriptome; D014916:Whole-Body Irradiation / Q000009:adverse effects
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger
keywords: Gene expression; Hematological acute radiation syndrome (HARS); Pancytopenia; miRNA