RETROVIRAL INTEGRATION WITHIN THE FLI-2 LOCUS RESULTS IN INACTIVATIONOF THE ERYTHROID TRANSCRIPTION FACTOR NF-E2 IN FRIEND ERYTHROLEUKEMIAS - EVIDENCE THAT NF-E2 IS ESSENTIAL FOR GLOBIN EXPRESSION

Activation of either Fli-1 or Spi-1 members of the ets family of trans cription factors as a result of retroviral insertion and mutational in activation of the p53 tumor suppresser gene play essential roles in th e multistage erythroleukemias induced in mice by various strains of Fr iend virus. We have previously identified another common site for prov irus integration, designated Fli-2 (Friend leukemia integration 2), in some erythroleukemia clones induced either by Friend murine leukemia virus (F-MuLV) or by the polycythemia-inducing strain of Friend virus complex (FV-P). Here we show that genomic sequences adjacent to Fli-2 correspond to the coding region of the erythroid-specific DNA binding protein NF-E2 p45. In one erythroleukemia cell line the expression of NF-E2 p45 is undetectable due to proviral integration in one allele an d loss of the other allele. The complete loss of NF-E2 p45 in this cel l line is associated with a drastic reduction in expression of the alp ha- and beta-globin genes that were partially restored by reintroducti on of the NF-E2 p45 gene. Taken together, these results provide direct evidence that NF-E2 gene is essential for globin transcription and su ggest that perturbation in expression of this transcription factor may contribute to erythroleukemia progression.