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7 January 2014 Radiologic Differences between Bone Marrow Stromal and Hematopoietic Progenitor Cell Lines from Fanconi Anemia (Fancd2–/–) Mice
Hebist Berhane, Michael W. Epperly, Julie Goff, Ronny Kalash, Shaonan Cao, Darcy Franicola, Xichen Zhang, Donna Shields, Frank Houghton, Hong Wang, Peter Wipf, Kalindi Parmar, Joel S. Greenberger
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Abstract

FancD2 plays a central role in the human Fanconi anemia DNA damage response (DDR) pathway. Fancd2–/– mice exhibit many features of human Fanconi anemia including cellular DNA repair defects. Whether the DNA repair defect in Fancd2–/– mice results in radiologic changes in all cell lineages is unknown. We measured stress of hematopoiesis in long-term marrow cultures and radiosensitivity in clonogenic survival curves, as well as comet tail intensity, total antioxidant stores and radiation-induced gene expression in hematopoietic progenitor compared to bone marrow stromal cell lines. We further evaluated radioprotection by a mitochondrial-targeted antioxidant GS-nitroxide, JP4-039. Hematopoiesis longevity in Fancd2–/– mouse long-term marrow cultures was diminished and bone marrow stromal cell lines were radiosensitive compared to Fancd2 / stromal cells (Fancd2–/– D0 = 1.4 ± 0.1 Gy, ñ = 5.0 ± 0.6 vs. Fancd2 / D0 = 1.6 ± 0.1 Gy, ñ = 6.7 ± 1.6), P = 0.0124 for D0 and P = 0.0023 for ñ, respectively). In contrast, Fancd2–/– IL-3-dependent hematopoietic progenitor cells were radioresistant (D0 = 1.71 ± 0.04 Gy and ñ = 5.07 ± 0.52) compared to Fancd2 / (D0 = 1.39 ± 0.09 Gy and ñ = 2.31 ± 0.85, P = 0.001 for D0). CFU-GM from freshly explanted Fancd2–/– marrow was also radioresistant. Consistent with radiosensitivity, irradiated Fancd2–/– stromal cells had higher DNA damage by comet tail intensity assay compared to Fancd2 / cells (P < 0.0001), slower DNA damage recovery, lower baseline total antioxidant capacity, enhanced radiation-induced depletion of antioxidants, and increased CDKN1A-p21 gene transcripts and protein. Consistent with radioresistance, Fancd2–/– IL-3-dependent hematopoietic cells had higher baseline and post irradiation total antioxidant capacity. While, there was no detectable alteration of radiation-induced cell cycle arrest with Fancd2–/– stromal cells, hematopoietic progenitor cells showed reduced G2/M cell cycle arrest. The absence of the mouse Fancd2 gene product confers radiosensitivity to bone marrow stromal but not hematopoietic progenitor cells.

Hebist Berhane, Michael W. Epperly, Julie Goff, Ronny Kalash, Shaonan Cao, Darcy Franicola, Xichen Zhang, Donna Shields, Frank Houghton, Hong Wang, Peter Wipf, Kalindi Parmar, and Joel S. Greenberger "Radiologic Differences between Bone Marrow Stromal and Hematopoietic Progenitor Cell Lines from Fanconi Anemia (Fancd2–/–) Mice," Radiation Research 181(1), 76-89, (7 January 2014). https://doi.org/10.1667/RR13405.1
Received: 16 May 2013; Accepted: 1 September 2013; Published: 7 January 2014
JOURNAL ARTICLE
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