Continuous Fli-1 expression plays an essential role in the proliferation and survival of F-MuLV-induced erythroleukemia and human erythroleukemia

• Published in: Leukemia Vol. 23; no. 7; pp. 1311 - 1319
• Main Authors: Cui, J-W, Vecchiarelli-Federico, L M, Li, Y-J, Wang, G-J, Ben-David, Y
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2009; Nature Publishing Group
• Subjects: Acute leukemia; Animals; Apoptosis; Base Sequence; Bcl-2 protein; Biological and medical sciences; Bone cancer; Cancer Research; Carcinogenesis; Carcinogens; Cell death; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cellular biology; Critical Care Medicine; DNA binding proteins; DNA Primers; Down-Regulation; Erythroleukemia; Ewing's sarcoma; Ewings sarcoma; EWS protein; FLI-1 protein; Friend murine leukemia virus; Gene expression; Genes; Genetic aspects; Health sciences; Hematologic and hematopoietic diseases; Hematology; Humans; Immunohistochemistry; Intensive; Internal Medicine; Leukemia; Leukemia Virus, Murine - pathogenicity; Leukemia, Erythroblastic, Acute - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Medicine; Medicine & Public Health; Mice; Oncology; original-article; Phenotypes; Physiological aspects; Proteins; Proto-Oncogene Protein c-fli-1 - genetics; Proto-Oncogene Protein c-fli-1 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; RNA Interference; RNA polymerase; RNA-mediated interference; Sarcoma; Survival; Tumors; Viruses; Canada; United States > US; RNAi; Fli-1; Engrailed; Friend erythroleukemia; erythroleukemia; Erythroleukemia; Human; Cell proliferation; RNA interference; Hematology; Transcription factor Fli1; Acute; Malignant hemopathy; Survival; Gene silencing; Myeloproliferative syndrome; M6 acute myelocytic leukemia; Cancer
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2009.20

Erythroleukemia induced by Friend Murine Leukemia Virus (F-MuLV) serves as a powerful tool for the study of multistage carcinogenesis and hematological malignancies in mice. Fli-1 , a proto-oncogene and member of the Ets family, is activated through viral integration in F-MuLV-induced erythroleukemia, and is the most critical event in the induction of this disease. Fli-1 aberrant regulation is also observed in human malignancies, including Ewing's sarcoma, which is often linked to expression of the EWS/Fli-1 fusion oncoprotein. Here we examined the effects of Fli-1 inhibition to further elucidate its role in these pathological occurrences. The constitutive suppression of Fli-1, through RNA interference (RNAi), inhibits growth and induces death in F-MuLV-induced erythroleukemia cells. Expression of a dominant negative protein Engrailed (En)/Fli-1 reduces proliferation of EWS/Fli-1-transformed NIH-3T3 cells, and both F-MuLV-induced and human erythroleukemia cells. F-MuLV-induced erythroleukemia cells also display increased apoptosis, associated with reduced expression of bcl-2 , a known fli-1 target gene. Introduction of En/Fli-1 into an F-MuLV-infected erythroblastic cell line induces differentiation, as shown by increased α-globin expression. These results suggest, for the first time, an essential role for continuous Fli-1 overexpression in the maintenance and survival of the malignant phenotype in murine and human erythroleukemias.