A CYTOKINE RECEPTOR ONCOGENE: ROLE IN LEUKEMOGENESIS (MEETING ABSTRACT)

Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.

A CYTOKINE RECEPTOR ONCOGENE: ROLE IN LEUKEMOGENESIS (MEETING ABSTRACT)

Fifteenth Symposium of the International Association for Comparative Research on Leukemia and Related Disease. October 6-11, 1991, Padova/Venice, Italy, p. 51, 1991.. Unique Identifier : AIDSLINE ICDB/92682402
Longmore G; Lodish H; Whitehead Inst. for Biomedical Res., MIT, Cambridge, MA

Abstract: Friend virus, a murine erythroleukemia virus, is a complex of two viruses: a replication-competent helper virus, Friend murine leukemia virus (F-MuLV) and a replication-defective retrovirus, Friend spleen focus-forming virus (F-SFFV). The pathologic consequences of Friend disease are determined by the genome of the defective F-SFFV. Sequence analysis of the defective F-SFFV genome has revealed mutations in all three viral genes (ie, gag, pol, env). Genetic evidence indicates that it is the env gene which is responsible for F-SFFV-induced erythroleukemia. The env gene of SFFV is thought to arise from a recombination between an ecotropic F-MuLV and dual-tropic env sequences that are endogenously inherited in mice. The env gene encodes for a membrane glycoprotein, gp55. Although only a small fraction of gp55 is processed from the endoplasmic reticulum to the plasma membrane, the latter component is essential for causing erythroleukemia. After reaching the cell surface, gp55 is slowly shed into the extracellular medium. Further genetic studies have suggested that the secreted form of gp55 may be essential in the erythroleukemic process. Recent biochemical and biologic data from our laboratory have shown that gp55 binds to and activates the EPOR. The gp55-EPOR interaction results in the ability of cells expressing both to proliferate in the absence of erythropoietin. Furthermore, we have shown that nontumorigenic pre-B cells (BA/F3) expressing gp55 and EPOR are tumorigenic when injected into syngeneic mice. Gp55 interaction with the EPOR results in increased stability of the EPOR protein and accumulation in the endoplasmic reticulum (ER), suggesting that gp55 may activate the EPOR in the ER. Erythroleukemia, as generated by the Friend virus, has two phases. An early phase (2-3 days) consists of a polyclonal erythroblastosis without any increase in cell self-renewal capacity or abrogation of commitment to differentiation. Eventually (14-21 days), a population of clonal, growth factor-independent cells that are blocked in differentiation at the proerythroblast stage develop. It is not clear whether gp55 is necessary for both phases of the disease. Possibly the gp55-EPOR interaction is necessary only for the early proliferative phase allowing for further genetic mutations to occur, resulting in a differentiation block and leukemia (multistep oncogenesis). Other genetic events, described in erythroleukemic cell lines derived from Friend virus infections, include a unique genomic insertion site for the SFFV provirus. This genomic locus spi-1 (SFFV proviral integration) following SFFV integration gives rise to DNA rearrangements with a resultant new gene transcript. No spi-1 rearrangements have been detected in other virally induced myeloid, lymphoid or erythroid tumors. The spi-1 gene product is a normally present transcriptional factor, PU-1, found in B cells and macrophages. Spi-1 (PU-1) has significant sequence homology to the DNA-binding domain of the ets oncogene family (avian leukemia virus E26). The functional significance of spi-1 expression in SFFV-induced erythroleukemia is unknown. Inactivation, deletions and point mutations in the suppressor oncogene p53 have been described. Again the functional significance of these mutations is not known. Possibly these rearrangements and mutations predispose cells for leukemic transformation (p53) and/or are responsible for the later phase of the disease resulting in differentiation arrest and leukemic progression (sp-1), consistent with the multistep nature of malignancy.

Keywords: Cell Differentiation DNA, Viral/GENETICS Gene Products, env/*GENETICS Gene Rearrangement Genome, Viral Leukemia, Erythroblastic, Acute/*GENETICS/PATHOLOGY Leukemia, Experimental/*GENETICS/PATHOLOGY Protein p53/GENETICS Proto-Oncogene Proteins/GENETICS Spleen Focus-Forming Viruses/*GENETICS Transcription Factor, Sp1/GENETICS ABSTRACT
920930
M9290917

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