Fv-2 locus controls expression of Friend spleen focus-forming virus-specific sequences in normal and infected mice

Abstract

We have recently demonstrated that normal hemopoietic cells express RNA sequences that are homologous to sequences specific for the Friend erythroleukemia virus genome [Bernstein, A., Gamble, C., Penrose, D. & Mak, T. W. (1979) Proc. NatL Acad. Sci. USA 76,[4455][4456][4457][4458][4459]. In this communication, we report that the Fv-2 locus, the major genetic determinant controlling host susceptibility to erythroleukemia induction by Friend leukemia virus, also controls the expression of endogenous sequences related to the replication-defective component of Friend leukemia virus, Friend spleen focus-forming virus (SFFV), in normal uninfected mice. Two independent congeneic pairs of mice [C57BL/6 (B6) and B6.S; B6 and B6.C(H_7b)J, differing only in a small region of the mouse genome including the Fv-2 locus, were used for this purpose. In -both cases, molecular hybridization analysis indicated that the presence of SFFV-related RNA sequences in normal mice was associated with the Fv-2s allele: bone marrow or spleen cellular RNA from Fv-2f B6 mice contained no detectable SFFV-related sequences, whereas their congeneic Fv-2ss pairs contained relatively high levels of these RNA sequences. The absence of these RNA sequences in Fv-27 mice was not due to deletion of these sequences from the DNA of Fv-2ff mice. Repopulation of lethall irradiated Fv-2r mice with syngeneic Fv-2f' bone marrow cells did not lead to any increase in-the levels of these SFFVrelated RNA sequences, suggesting that the expression of these sequences is still reduced or inhibited in actively cycling hemopoietic cells. Infection with Friend leukemia virus resulted in the appearance of high levels of RNA homologous to SFFV-specific sequences in the leukemic spleens of B6.S (Fv-2ss) mice, whereas these cellular RNA sequences could not be detected in the spleens of Friend virus-infected B6 (Fv-2ff) mice. The demonstration that the same gene locus controls both the expression of exogenous SFFV-specific sequences and erythroleukemia induction by Friend leukemia virus suggests that these sequences may be necessary for erythroleukemic transformation. In addition, the finding that the Fv-2 gene locus controls the expression of endogenous SFFV-related sequences suggests that these sequences may also be involved in normal hemopoiesis. The genomes of a number of avian and murine sarcoma viruses contain unique sequences involved in the rapid malignant transformation of fibroblasts (1-3). These sarcoma virus-specific sequences have been found to be present in normal host cell DNA (4, 5). In addition, sequences related to the src gene of Rous sarcoma virus appear to be transcribed (6) and translated (7, 8) in normal chicken embryo fibroblasts, although a role for these sequences in normal cell function has not yet been identified. The genome of the replication-defective component of the polycythemic strain of Friend leukemia virus (FLV), Friend spleen focus-forming virus (SFFV), has also been shown to contain specific sequences (9-11). These sequences ar...

Complete nucleotide sequence of an infectious clone of Friend spleen focus-forming provirus: gp55 is an envelope fusion glycoprotein.

“…SFFV induces an unusual disease consisting of an early (1-2 weeks) proliferation and differentiation of erythroid cells (2,8) and a late stage when transformed cells able to form tumors and permanent cell lines appear (9,10). Which of the SFFV or F-MuLV viral genomes induces the progression of transformation has not been determined, but it is known that SFFV is responsible for the early stage (8) and is under the control of the same host factors that influence normal hemopoietic development (4,(11)(12)(13). Recombinant DNA experiments have suggested that gp55, the product of the env gene, may be required for the initial cellular proliferation (14).…”

“…(12) and the finding that SFFV infection extends the self-renewal capacity of hemopoietic stem cells in vivo (42). Furthermore, the major locus that controls the susceptibility of mice to Friend disease (Fv-2) controls the expression of endogenous SFFV-related sequences in hemopoietic cells (4,11) as well as the rate of proliferation of erythroid precursor cells (13).…”

Isolation and induction of erythroleukemic cell lines with properties of erythroid progenitor burst-forming cell (BFU-E) and erythroid precursor cell (CFU-E).

“…In addition, the F-MuLVinduced erythroleukemia is also governed by developmental controls, as only newborn mice of Fv-6ss genotype are susceptible (23,26,28,39). Developmental controls can affect susceptibility by modulating the hemopoietic composition as adult mice of both Fv-6ss or Fv-6rr genotypes can be rendered partially susceptible by external agents known to modulate the hemopoietic compartment (28,42,44,45).…”

“…Steel, w, and H-2) are known to affect normal development as well (44,46,47), suggesting that there is a close relationship between the controls of normal and viral-induced hemopoiesis. More recently, it has been proposed that two gene loci, Fv-2 (43,45,48) and 50), which were discovered originally as determinants affecting viral-induced hemopoiesis, may have roles in normal hemopoietic development (30,44,45,48). This type of mechanism may play an important role in the control of other normal or viral-induced hemopoietic developments.…”

Strain Difference in Immune Response of the Rat to NRK Cells Infected with Spleen Focus-forming Virus of the Friend Leukaemia Virus Complex

“…In both strains, F-MuLV grew well, but SFFV did not. Mak et al (1979) detected SFFV-related RNA sequences in FLV-susceptible normal mice (Fv-2 ss genotype), but not in resistant ones . Glycoprotein gp55 is coded for by an SFFVspecific RNA sequence (Yoshida & Yoshikura, 1980).…”