Ionizing radiation and busulfan induce premature senescence in murine bone marrow hematopoietic cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2003-09, Vol.63 (17), p.5414-5419
• Main Authors: AIMIN MENG, YONG WANG, VAN ZANT, Gary, DAOHONG ZHOU
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Apoptosis - drug effects; Apoptosis - radiation effects; Biological and medical sciences; Busulfan - pharmacology; Cellular Senescence - drug effects; Cellular Senescence - radiation effects; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p21; Cyclins - biosynthesis; Cyclins - genetics; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - radiation effects; Male; Medical sciences; Mice; Mice, Inbred C57BL; Pharmacology. Drug treatments; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Tumor Suppressor Protein p14ARF - biosynthesis; Tumor Suppressor Protein p14ARF - genetics; Tumor Suppressor Protein p53 - biosynthesis; Tumor Suppressor Protein p53 - genetics
• ISSN: 0008-5472; 1538-7445

Exposure of murine bone marrow (BM) cells to ionizing radiation (IR; 4 Gy) resulted in >95% inhibition of the frequency of various day types of cobblestone area-forming cells in association with the induction of apoptosis in hematopoietic stem cell alike cells (Lin(-) ScaI(+) c-kit(+) cells; IR: 64.8 +/- 0.4% versus control: 20.4 +/- 0.5%; P < 0.001) and progenitors (Lin(-) ScaI(-) c-kit(+) cells; IR: 46.2 +/- 1.4% versus control: 7.8 +/- 0.5%; P < 0.001). Incubation of murine BM cells with busulfan (BU; 30 micro M) for 6 h also inhibited the cobblestone area-forming cell frequency but failed to cause a significant increase in apoptosis in these two types of hematopoietic cells. After 5 weeks of long-term BM cell culture, 33% and 72% of hematopoietic cells survived IR- and BU-induced damage, respectively, as compared with control cells, but they could not form colony forming units-granulocyte macrophages. Moreover, these surviving cells expressed an increased level of senescence-associated beta-galactosidase, p16(Ink4a), and p19(Arf). These findings suggest that IR inhibits the function of hematopoietic stem cell alike cells and progenitors primarily by inducing apoptosis, whereas BU does so mainly by inducing premature senescence. In addition, induction of premature senescence in BM hematopoietic cells also contributes to IR-induced inhibition of their hematopoietic function. Interestingly, the induction of hematopoietic cell senescence by IR, but not by BU, was associated with an elevation in p53 and p21(Cip1/Waf1) expression. This suggests that IR induces hematopoietic cell senescence in a p53-p21(Cip1/Waf1)-dependent manner, whereas the induction of senescence by BU bypasses the p53-p21(Cip1/Waf1) pathway.