Quantitative colony method for tumorigenic cells transformed by two distinct strains of Friend leukemia virus

Mager, Dixie L.; Mak, Tak W.; Bernstein, Alan

doi:10.1073/pnas.78.3.1703

Cited by 61 publications

(57 citation statements)

References 25 publications

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“…The autonomous proliferation and di erentiation of proerythroblasts is caused by a direct interaction between the gp55 glycoprotein encoded by the SFFV env gene and the Epo receptor which becomes constitutively activated (Aizawa et al, 1990;Li et al, 1990;Longmore and Lodish, 1991). The late stage of the disease is characterized by the emergence of a clonal population of malignant tumorigenic proerythroblasts arrested in their di erentiation process (Mager et al, 1981;Wendling et al, 1981). Extensive studies on the genetic alterations involved in the progression of SFFV-infected proerythroblasts towards malignancy have identi®ed two cellular genes spi-1 and p53, mutated in the Friend tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Spi-1 transgenic mice develop a clonal erythroleukemia which does not depend on p53 mutation

et al. 1998

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Spi-1 transcriptional activation and wild-type p53 extinction are two oncogenic alterations involved in the malignant transformation of erythroblasts during the Friend acute erythroleukemia. To dissect the contribution of these alterations in the deregulation of the di erentiation and proliferation of erythroblasts, we generated spi-1 transgenic mice. Analysis of these animals revealed that Spi-1 overexpression was directly involved in the block of proerythroblast di erentiation. However, the erythroleukemia that develops in these animals evolved in two steps. During the early step (HS1 step), non tumorigenic proerythroblasts remained strictly dependent upon erythropoietin (Epo) for their survival and proliferation. Later on, Epo-independent and tumorigenic proerythroblasts emerged (HS2 step) suggesting that other oncogenes cooperate with Spi-1 to lead to a fully malignant phenotype. By provirus tagging, we demonstrate that the HS1 step was clonal indicating that a cell selection must occur in vivo. Analysis of the nature of p53 in both the in vivo HS1 and HS2 proerythroblasts and in cultured erythroblastic cell lines showed that ± p53 was normal in the HS1 primary tissues but was mutated in the HS1 cultured cell lines ± p53 was frequently altered in HS2 primary tissues but was found normal in some mice. These data indicate that (i) the blockage of the erythroblast di erentiation by Spi-1 occurs independently of p53 alteration (ii) p53 alteration is not necessary to confer Epo independence and tumorigenicity to spi-1 transgenic proerythroblasts.

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Section: Introductionmentioning

confidence: 99%

Spi-1 transgenic mice develop a clonal erythroleukemia which does not depend on p53 mutation

et al. 1998

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“…This initial phase is induced by the gp55 glycoprotein encoded by the SFFV env gene which constitutively activates the Epo receptor (Aizawa et al, 1990;Li et al, 1990). During a later stage, a clonal population of proerythroblasts emerge that are arrested in their di erentiation and tumorigenic in vivo (Mager et al, 1981;Wendling et al, 1981). In these tumor cells, two recurrent genetic alterations have been identi®ed: a transcriptional dysregulation of the spi-1 gene by a SFFV insertional mutagenesis (MoreauGachelin et al, 1988) and the extinction of the p53 gene because of allelic deletions or punctual mutations (Ben-David et al, 1988;Mowat et al, 1985;Munroe et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Germ-line deletion of p53 reveals a multistage tumor progression in spi-1/PU.1 transgenic proerythroblasts

et al. 2001

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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-de®cient mice. Three classes of spi-1 transgenic mice di ering in their p53 functional status (p53 +/+ , p53 +/7 and p53 7/7 ) 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 +/7 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 7/7 spi-1-Tg mice developed erythroleukemia with a total incidence and a reduced latency compared to the two other genotypes. Unexpectedly, 50% of p53 7/7 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 ®ndings 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. Oncogene (2001) 20, 5484 ± 5492.

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“…In contrast, the later stages of Friend disease are characterized by the presence of transplantable, immortal erythroleukemia cells that can be detected by their ability to produce tumors in syngeneic hosts (13)(14)(15)(16), spleen colonies in mutant SJ/Sid mice (17), or large colonies of relatively undifferentiated cells in methylcellulose within 14 days after plating (18,19). The development of clonogenic assays for cells in both the preleukemic and leukemic stages of this disease make the Friend system an excellent model for analysis of multistage malignancies.…”

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confidence: 99%

Induction of the early stages of Friend erythroleukemia with helper-free Friend spleen focus-forming virus.

Berger¹,

Sanderson²,

Bernstein³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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The polycythemia-inducing strain of Friend virus (FV-P) causes a multistage erythroleukemia in susceptible mice. FV-P is a complex of two viruses, a replication-competent virus [Friend murine leukemia virus (F-MuLV)] and a replication-defective spleen focus-forming virus (SFFVp). We have addressed directly the role of SFFVp in the induction of the early stages of Friend disease by constructing stocks of SFFVp free of detectable F-MuLV, using a recently described retroviral helper-cell line. These preparations are capable of inducing erythroid bursts (vBFU-E) whose inducibility, kinetics, and responsiveness to erythropoietin suggest that they are very similar, if not identical, to the vBFU-E induced by FV-P. Singleiijections of helper-free SFFVp had no apparent effects in vivo, although the addition ofexogenous helper virus to the inoculum resulted in the induction of classic Friend disease. Increasing the effective titer by giving mice five daily virus injections resulted in the induction of splenomegaly and a large increase in the number of erythroid colony-forming units that were independent of erythropoietin. When the injections were discontinued, the spleens regressed and all the mice survived.When the injections were continued, all the mice died within 25 days of the first injection. These results demonstrate that SFFVp alone can alter the growth characteristics of erythroid progenitors and is directly responsible for the induction of vBFU-E in vitro and the erythroid hyperplasia in vivo. They also demonstrate that the initial polyclonal stage of Friend disease is reversible and can be reproduced by using prepara-

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Quantitative colony method for tumorigenic cells transformed by two distinct strains of Friend leukemia virus

Cited by 61 publications

References 25 publications

Spi-1 transgenic mice develop a clonal erythroleukemia which does not depend on p53 mutation

Spi-1 transgenic mice develop a clonal erythroleukemia which does not depend on p53 mutation

Germ-line deletion of p53 reveals a multistage tumor progression in spi-1/PU.1 transgenic proerythroblasts

Induction of the early stages of Friend erythroleukemia with helper-free Friend spleen focus-forming virus.

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