p45NFE2 Is a Negative Regulator of Erythroid Proliferation Which Contributes to the Progression of Friend Virus-Induced Erythroleukemias

YJ Li, RR Higgins, BJ Pak, RA Shivdasani… - … and cellular biology, 2001 - Taylor & Francis
YJ Li, RR Higgins, BJ Pak, RA Shivdasani, PA Ney, M Archer, Y Ben-David
Molecular and cellular biology, 2001Taylor & Francis
In previous studies, we identified a common site of retroviral integration designated Fli-2 in
Friend murine leukemia virus (F-MuLV)-induced erythroleukemia cell lines. Insertion of F-
MuLV at the Fli-2 locus, which was associated with the loss of the second allele, resulted in
the inactivation of the erythroid cell-and megakaryocyte-specific gene p45 NFE2. Frequent
disruption of p45 NFE2 due to proviral insertion suggests a role for this transcription factor in
the progression of Friend virus-induced erythroleukemias. To assess this possibility …
In previous studies, we identified a common site of retroviral integration designated Fli-2 in Friend murine leukemia virus (F-MuLV)-induced erythroleukemia cell lines. Insertion of F-MuLV at the Fli-2 locus, which was associated with the loss of the second allele, resulted in the inactivation of the erythroid cell- and megakaryocyte-specific genep45 NFE2 . Frequent disruption ofp45 NFE2 due to proviral insertion suggests a role for this transcription factor in the progression of Friend virus-induced erythroleukemias. To assess this possibility, erythroleukemia was induced by F-MuLV in p45 NFE2 mutant mice. Sincep45 NFE2 homozygous mice mostly die at birth, erythroleukemia was induced in +/− and +/+ mice. We demonstrate that +/− mice succumb to the disease moderately but significantly faster than +/+ mice. In addition, the spleens of +/− mice were significantly larger than those of +/+ mice. Of the 37 tumors generated from the +/− and +/+ mice, 10 gave rise to cell lines, all of which were derived from +/− mice. Establishment in culture was associated with the loss of the remaining wild-typep45 NFE2 allele in 9 of 10 of these cell lines. The loss of a functional p45NFE2 in these cell lines was associated with a marked reduction in globin gene expression. Expression of wild-typep45 NFE2 in the nonproducer erythroleukemic cells resulted in reduced cell growth and restored the expression of globin genes. Similarly, the expression ofp45 NFE2 in these cells also slows tumor growth in vivo. These results indicate thatp45 NFE2 functions as an inhibitor of erythroid cell growth and that perturbation of its expression contributes to the progression of Friend erythroleukemia.
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