Loss of p53 in F-MuLV induced-erythroleukemias accelerates the acquisition of mutational events that confers immortality and growth factor independence.
Erythroleukemias induced by Friend Murine Leukemia Virus (F-MuLV) involve the insertional activation of the proto-oncogene Fli-1, and the inactivation of the p53 tumor suppressor gene. While the activation of Fli-1 is an early, primary transforming event, p53 mutations are correlated with the immortalization of erythroleukemic cells in culture. In this study we have further analysed the role of p53 loss in F-MuLV induced erythroleukemias by examining the progression of this disease in p53 deficient mice. We found that p53-/- mice succumb to the disease more rapidly than p53+/+ littermates. Additionally, of the 112 tumors generated, 19 gave rise to immortal cell lines, eight of which were derived from p53-/- mice, and ten of which were from p53+/- mice. The ability of these primary tumor cells to grow in culture was associated with the complete loss of wild-type p53 in these cell lines. However, cells from many of the tumors induced in p53-/- hosts did not survive in vitro. These results suggest that the loss of p53 does not directly immortalize tumor cells. Instead, we have evidence to suggest that the loss of p53 promotes the accumulation of mutations that are required for survival in culture and that are capable of accelerating tumor progression in vivo. Indeed, mutations causing expression of the growth factor gene erythropoietin (Epo), were detected in two of seven Epo-independent cell lines from p53 deficient primary erythroleukemias. Moreover, the mechanism of activation of the Epo gene in one of these two Epo-independent cell lines involved genomic rearrangement, that is a hallmark of genetic instability. We propose that, in F-MuLV induced-erythroleukemias, p53 loss may encourage the accumulation of further mutations, subsequently conferring a growth advantage and immortality to the transformed erythroblasts.
Wong
K S
KS
Division of Cancer Biology, Sunnybrook and Women's College Health Sciences Centre, Research Building, S-Wing, S-218, Toronto, Ontario, Canada, M4N 3M5.
Li
Y J
YJ
Howard
J
J
Ben-David
Y
Y
D000818:Animals; D000831:Animals, Newborn; D001798:Blood Proteins / Q000096:biosynthesis / Q000235:genetics; D002455:Cell Division; D016922:Cellular Senescence; D004268:DNA-Binding Proteins / Q000502:physiology; D018450:Disease Progression; D015672:Erythroid Precursor Cells / Q000378:metabolism* / Q000821:virology; D004921:Erythropoietin / Q000494:pharmacology; D005260:Female; D005622:Friend murine leukemia virus / Q000502:physiology*; D017353:Gene Deletion; D015973:Gene Expression Regulation, Leukemic; D016158:Genes, p53; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics* / Q000821:virology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016296:Mutagenesis / Q000235:genetics*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D012192:Retroviridae Infections / Q000235:genetics* / Q000821:virology; D015534:Trans-Activators / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000637:transplantation; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency; D014412:Tumor Virus Infections / Q000235:genetics* / Q000821:virology
D001798:Blood Proteins; D004268:DNA-Binding Proteins; C497426:Fli1 protein, mouse; D009363:Neoplasm Proteins; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D004921:Erythropoietin