Expression of Transfected Recombinant Oncogenes Increases Radiation Resistance of Clonal Hematopoietic and Fibroblast Cell Lines Selectively at Clinical Low Dose Rate

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Abstract
To determine the effect of oncogene expression on .gamma. radiation sensitivity to hematopoietic compared to fibroblastic cells, we selected clonal sublines of an interleukin-3 (IL-3)-dependent hematopoietic progenitor cell line 32D cl 3 and nIH/3T3 embryo fibroblasts cells following transfection with each oncogene linked to the mycophenolic acid resistance gene. Each mycophenolic acid-resistant subclone demonstrated high levels of specific poly(A)+ mRNA for each oncogene. The parent line 32D cl 3 demonstrated similar radiosensitivity at 116 cGy/min (Do 126, .hivin.n 1.17) compared to 5 cGy/min (Do 123, .hivin.n 1.65). This pattern was not altered in subclones of 32D cl 3 cells transfected with the epidermal growth factor(EGF) receptor gene and grown in EGF (at 116 cGy/min Do 122.4, .hivin.n 1.79, at 5 cGy/min Do 135, .hivin.n 1.43). In contrast, expression of the transfected oncogenes v-erb-B, v-abl, or v-src conferred significant radioresistance at 5 cGy/min dose rate (Do 194, .hivin.n 1.77; Do 165.5, .hivin.n 1.56; Do 171, .hivin.1.28, respectively). With the exception of v-sis, oncogene expression resulted in nonautocrine factor independence of 32D cl 3 subclones, and production of donor origin tumors in syngeneic newborn or adult mice. Two rare spontaneous factor-independent subclones of 32D cl 3 were also tested. Nonautocrine clone 32D cl 2 demonstrated significantly increased radioresistance at low dose rate (Do 186, .hivin.n 1.63), while autocrine (IL-3 producing) subclone 32D cl 4 revealed no significant increase in radioresistance at 5 cGy/min. The parent fibroblast cell line NIH/3T3 showed an intrinsic relative radioresistance at low dose rate (at 5 cGy/min Do 157.3 .hivin.n 1.81, compared to 116 cGy/min Do 134.3, .hivin.n 1.57). Expression of NIH 3T3 of transfected oncogenes v-abl, v-fms, v-fos, or H-ras increased radioresistance at low dose rate (Do 208.6, .hivin.n 1.61; Do 206.6, .hivin.n 1.51; Do 167.5, .hivin.n 1.85; and Do 206.8, .hivin.n 1.08, respectively). Thus expression of each of several oncogenes induces resistance to .gamma. irradiation at 5 cGy/min in hematopoietic and fibroblast cell lines. These data may help explain the clinical recurrence of oncogene-expressing leukemia and lymphoma cells after marrow stem cell ablative doses of low-dose-rate total-body irradiation.

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