Fli-1 overexpression in hematopoietic progenitors deregulates T cell development and induces pre-T cell lymphoblastic leukaemia/lymphoma

• Published in: PloS one Vol. 8; no. 5; p. e62346
• Main Authors: Smeets, Monique F M A, Chan, Angela C, Dagger, Samantha, Bradley, Cara K, Wei, Andrew, Izon, David J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07-05-2013; Public Library of Science (PLoS)
• Subjects: Animals; Apoptosis; B cells; Bcl-2 protein; Biology; Bone marrow; Cancer; Carcinogenesis - immunology; CD4 antigen; CD8 antigen; Deregulation; ETS protein; FLI-1 protein; Flow cytometry; Gene Expression; Genes; Genomes; Hematology; Hematopoietic Stem Cells - metabolism; Hemopoiesis; Humans; Immunoglobulins; Immunology; Intracellular Space - genetics; Leukemia; Liver transplants; Lymphatic system; Lymphocytes; Lymphocytes T; Lymphoma; Medicine; Mice; Mice, Inbred C57BL; Mutation; Notch1 protein; Organ Specificity; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - immunology; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Proto-Oncogene Protein c-fli-1 - genetics; Proto-Oncogene Proteins c-bcl-2 - genetics; Receptor, Notch1 - genetics; RNA, Messenger - genetics; Signal transduction; Signaling; Spleen; Stem cell transplantation; T cell receptors; T cells; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Target recognition; Tissues; Transcription factors; Tumors; Up-Regulation - immunology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0062346

The Ets transcription factor Fli-1 is preferentially expressed in hematopoietic tissues and cells, including immature T cells, but the role of Fli-1 in T cell development has not been closely examined. To address this we retrovirally overexpressed Fli-1 in various in vitro and in vivo settings and analysed its effect on T cell development. We found that Fli-1 overexpression perturbed the DN to DP transition and inhibited CD4 development whilst enhancing CD8 development both in vitro and in vivo. Surprisingly, Fli-1 overexpression in vivo eventuated in development of pre-T cell lymphoblastic leukaemia/lymphoma (pre-T LBL). Known Fli-1 target genes such as the pro-survival Bcl-2 family members were not found to be upregulated. In contrast, we found increased NOTCH1 expression in all Fli-1 T cells and detected Notch1 mutations in all tumours. These data show a novel function for Fli-1 in T cell development and leukaemogenesis and provide a new mouse model of pre-T LBL to identify treatment options that target the Fli-1 and Notch1 signalling pathways.