Abstract
Abstract Serpins are a superfamily of serine protease inhibitors that regulate proteolytic pathways by utilizing a conformational change to bind to and inhibit their target peptidases. Currently 36 human serpins have been identified, but the biological roles of most are not fully understood (Silverman et al., J Biol Chem. 285(32):24299-305, 2010). Serpinb3a (the mouse orthologue of human SERPINB3 and -B4) is an intracellular serpin and inhibits both serine and cysteine peptidases invitro. We now report radioresistance of Serpinb3a-/- mice and their hematopoietic progenitor cells. Serpinb3a-/- and control Balb/c mice were irradiated to a dose of 8.0 Gy total body irradiation and followed for the development of the hematopoietic syndrome. Long Term Bone Marrow Cultures (LTBMCs) were established from the bone marrow flushed from the femurs and tibias of Serpinb3a-/- and Balb/c mice. Irradiation survival curves were performed on bone marrow stromal cell lines established from the LTBMCs and on fresh bone marrow isolated from the femurs of sacrificed Serpinb3a-/- and Balb/c mice. Colony forming unit granulocyte-macrophage (CFU-GM) colonies of 50 cells or greater were counted. The data from 3 experiments were analyzed using linear quadratic and single-hit, multi-target models. Serpinb3a-/- mice showed increased survival following 8.0 Gy TBI compared to Balb/c mice (p < 0.0001). CFU-GM from Serpinb3a-/- were radioresistant compared to Balb/c marrow (ň = 4.9 ± 1.4 and 1.4 ± 0.1, p = 0.0451, respectively). Serpinb3a-/- bone marrow stromal cells were radioresistant with an increased Do (1.97 + 0.11 Gy) compared to bone marrow stromal cells from Balb/c mice (Do = 1.45 + 0.03 Gy, p = 0.0113). Loss of Serpinb3a provides a radiation survival advantage, increases radioresistance of both hematopoietic progenitor cells and marrow stromal cells, and may lead to identification of new targets for design of radiation mitigator drugs. This research was supported by grant NIAID/NIH U19-A168021. Citation Format: Stephanie Thermozier, Michael Epperly, Darcy Franicola, Xichen Zhang, Renee Fisher, Donna Shields, Hong Wang, John Willis, Cliff Luke, Gary Silverman, Joel Greenberger. Serpinb3a-/- mice are radioresistant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2913.
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