Germ-line deletion of p53 reveals a multistage tumor progression in spi-1/PU.1 transgenic proerythroblasts.
Activation of the spi-1/PU.1 proto-oncogene and loss of p53 function are genetic alterations associated with the emergence of Friend malignant erythroleukemic cells. To address the role of p53 during erythroleukemogenesis, spi-1 transgenic mice (spi-1-Tg) which develop erythroleukemia were bred with p53-deficient mice. Three classes of spi-1 transgenic mice differing in their p53 functional status (p53(+/+), p53(+/-) and p53(-/-)) were generated. These mice developed a unique pattern of erythroleukemia. In wild-type p53 spi-1-Tg mice, none of the primary erythroleukemic spleen cells displayed autonomous growth in vitro and in vivo. In contrast, in p53(+/-) spi-1-Tg mice, erythroleukemic cells gave rise to growth factor-independent cell lines and generated tumors in vivo. Malignancy was associated with loss of the wild-type p53 allele. The p53(-/-) spi-1-Tg mice developed erythroleukemia with a total incidence and a reduced latency compared to the two other genotypes. Unexpectedly, 50% of p53(-/-) spi-1-Tg erythroleukemic spleens generated cell lines that were strictly dependent upon erythropoietin (Epo) for proliferation, whereas the remainder proliferated independently of cytokines. Moreover, only 70% of these spleen cells were tumorigenic. These findings indicate that p53 germ-line deletion did not confer malignancy to spi-1-transgenic proerythroblasts. Moreover Epo independence and tumorigenicity appear as separable phenotypic characteristics revealing that the spi-1-Tg proerythroblasts progress towards malignancy through multiple oncogenic events.
Scolan
E L
EL
Inserm U528, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
Wendling
F
F
Barnache
S
S
Denis
N
N
Tulliez
M
M
Vainchenker
W
W
Moreau-Gachelin
F
F
D000818:Animals; D000831:Animals, Newborn; D001773:Blood Cells / Q000166:cytology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D018450:Disease Progression; D015672:Erythroid Precursor Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D018095:Germ-Line Mutation; D004915:Leukemia, Erythroblastic, Acute / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D015996:Survival Rate; D015534:Trans-Activators / Q000235:genetics*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D000099232:Proto-Oncogene Protein Spi-1
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011518:Proto-Oncogene Proteins; D012334:RNA, Neoplasm; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D000099232:Proto-Oncogene Protein Spi-1; C493957:Cdkn1a protein, mouse