Spi-1 transgenic mice develop a clonal erythroleukemia which does not depend on p53 mutation.
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 differentiation 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 differentiation. 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 differentiation 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.
Barnache
S
S
INSERM U248, Institut Curie, Paris, France.
Wendling
F
F
Lacombe
C
C
Denis
N
N
Titeux
M
M
Vainchenker
W
W
Moreau-Gachelin
F
F
D000818:Animals; D002999:Clone Cells; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D000099232:Proto-Oncogene Protein Spi-1
D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D000099232:Proto-Oncogene Protein Spi-1