Erythroleukemia induction by Friend murine leukemia virus: insertional activation of a new member of the ets gene family, Fli-1, closely linked to c-ets-1.

Abstract

The retroviral integration siteThe hematopoietic system is composed of a hierarchy of cells, ranging from the pluripotent stem cell, committed myeloid and lymphoid progenitor cells, to terminally differentiated blood cells (Metcalf 1988;Sachs 1987). The molecular mechanisms that control the developmental and proliferative decisions of the pluripotent hematopoietic stem cell are largely unknown. The extreme cellular heterogeneity of hematopoietic populations, combined with the low frequency of stem cells, has hampered experimental approaches to this problem. The generation of mutations that affect stem cell function and the molecular analysis of existing developmental mutations that control hematopoiesis (Pawson and Bernstein 1990) provide two powerful genetic strategies for identifying and characterizing the genes that control normal blood cell formation. In addition, because cellular genes involved in leukemic transformation may also have a role in regulating normal stem cell function, the identification of such genes may provide insights into both normal and leukemic hematopoiesis. Transformation by certain retroviruses can involve the integration of proviral DNA near or within specific cellular genes. Such integration events most frequently lead to the elevated expression of these genes (for review, see in Peters 1990), although the tumor suppressor gene p53 can also be inactivated by retroviral integration of the Friend leukemia virus (Ben-David et al. 1988, 1990b. The analysis of common retroviral integration events can, therefore, be used to identify and clone novel transforming genes involved in tumorigenesis. Using this approach, a large number of genes important in the leukemic transformation of hematopoietic cells, including have been isolated (Peters 1990).The Fli-1 and Spi-1 genes have been shown by us and others (Moreau-Gachelin et al. 1988; Ben-David et al. 1990) to be involved in erythroleukemia induction by various strains of Friend leukemia virus. Fli-1 (Friend leukemia integration-site 1) is rearranged in 75% of independently isolated erythroleukemic clones from mice inoculated at birth with the replication-competent Cold Spring Harbor Laboratory Press on May 9, 2018 -Published by genesdev.cshlp.org Downloaded from

Molecular phylogeny of the ETS gene family

“…For example, in Ewing sarcomas and related tumors, speci®c chromosomal translocations induce the fusion of carboxy-terminal domains of Fli-1, Erg, Etv-1 and Pea3, and recently Fev, with the amino-terminal half of Ews, an RNA binding protein encoded by the ews gene (Delattre et al, 1992;Sorensen et al, 1994;Jeon et al, 1996;Urano et al, 1996;Peter et al, 1997). By contrast, the members of distinct subfamilies, the¯i-1 and spi-1 genes, share the property to be targets of viral integration and overexpressed in the leukemic cells of the erythroleukemias induced in mice by the Friend helper virus and the Friend virus complex, respectively (Ben-David et al, 1991;Moreau-Gachelin et al, 1988). By contrast, inside the ELK group, the two paralogous elk and sap-1 gene products exhibit di erential DNA binding speci®cities (Shore and Sharroks, 1995).…”

Ets factors and a newly identified polymorphism regulate Fli1 promoter activity in lymphocytes

“…Murine Fli1 was first identified as a proto-oncogene as a site for retroviral integration of Friend virus-induced erythroleukemias (Ben-David et al, 1990). It is expressed in hematopoietic tissues in both embryos and adults, as well as in other tissues (Ben-David et al, 1991;Melet et al, 1996;Watson et al, 1992) and is essential for embryogenesis (Hart et al, 2000;Masuya et al, 2005;Spyropoulos et al, 2000). During lymphocyte development, Fli1 is first detected in the developing spleen and thymus of the embryo and later in mature B cells and throughout T cell development (Anderson et al, 1999;Melet et al, 1996), but is down-regulated in activated T cells (Mao et al, 1994;Zhang and Watson, 2005).…”

Fli-1b is generated by usage of differential splicing and alternative promoter

“…Analyses of human and mouse Fli-1 cDNA sequences placed them in the ETS gene family which shows high homology within their DNA binding (ETS) domain (Ben-David et al, 1991;Prasad et al, 1992) and codes for di erent sequence-speci®c transcriptional activators. The superfamily of ETS genes includes several members: c-ets-1 (Reddy and Rao, 1988;Chen, 1988), ets-2 Boulukos et al, 1988), erg Rao et al, 1987), Elk-1 and Elk-2 (Rao et al, 1989), Pu.1/Spi-1 and Spi-1B (Goebl et al, 1990;Klemsz et al, 1990;Ray et al, 1992), E-74 (Burtis et al, 1990) Sap-1 and Sap-2 (Dalton and Triesman, 1992), GABP a (LaMarco et al, 1991), Elf-1 , PEA-3 (Xin et al, 1992), Fli-1 (Ben-David et al, 1990;Prasad et al, 1992), D-elg (Pribyl et al, 1988), ER-81 and ER-71 (Brown and McKnight, 1992), Tel (Golub et al, 1994), ERP (Lopez et al, 1994) and ETV-1 (Jeon et al, 1995).…”

“…Interestingly, Spi-1 is not found to be rearranged in erythroleukemias induced by F-MuLV nor is Fli-1 shown to be rearranged in SFFV-induced leukemias, suggesting the high speci®city of integration/activation of these genes. Mouse Fli-1 locus has been localized to chromosome 9 and its human homologue to chromosome 11, syntenic with mouse chromosome (Ben-David et al, 1991;Delattre et al, 1992;Baud et al, 1991), frequently involved in rearrangements in many human leukemias, lymphomas and sarcomas (Haluska et al, 1986;Yunis et al, 1986;Selleri et al, 1991).…”

“…Molecular characterization of these Ewing family of tumors revealed fusion of the EWS gene on chromosome 22, with either Fli-1 or erg genes located on chromosomes 11 and 21 respectively. Previously Fli-1 and Erg genes have been cloned by us and others (Ben-David et al, 1991;Prasad et al, 1992;Reddy et al, 1987) and the functional analysis of these proteins revealed that these proteins code for sequence-speci®c transcriptional activators with two transactivation domains present at amino-and carboxy-termini (Siddique et al, 1993;Rao et al, 1993). We and others have shown that EWS-Fli-1 and EWS-erg proteins encode transcriptional activators Baily et al, 1994) and these aberrant proteins show altered DNA binding and transactivation properties compared to normal Fli-1 and erg proteins.…”