Resistance to Friend Virus-Induced Erythroleukemia in W / W ^v Mice Is Caused by a Spleen-Specific Defect Which Results in a Severe Reduction in Target Cells and a Lack of Sf-Stk Expression

Friend Virus Utilizes the BMP4-Dependent Stress Erythropoiesis Pathway To Induce Erythroleukemia

“…These progenitors exhibit properties distinct from those of bone marrow steady-state BFU-E in that they require only Epo to rapidly generate large colonies. Analysis of spleen cell populations showed that the BMP4 R stress BFU-E are present in the spleen MEP fraction, which are also the targets for FV in the spleen, suggesting that the BMP4-dependent stress erythropoiesis pathway is involved in the pathogenesis of Friend erythroleukemia (45). This link between FV and stress erythropoiesis also is supported by the observation that f/f mice are resistant to FV-induced erythroleukemia (2).…”

“…Infection with FV leads to BMP4 expression in the spleens of wild-type mice but not f/f mutant mice, suggesting that in addition to the target cell defect, f/f mice have a defect in the spleen microenvironment. Our earlier analysis of W/W v mice identified MEPs as the target cells in the spleen (45). Here we identify two distinct populations of target cells in the bone marrow, one that expresses Sf-Stk and forms Epo-independent (Epo ind ) BFU-E following FV infection and a second population that migrates to the spleen following infection and induces BMP4 expression.…”

“…The original work demonstrating that W and Sl mice were resistant to FV suggested that the defect in erythropoiesis that leads to the severe anemia was responsible for the resistance (5,40). However, recent work from our laboratory has demonstrated that pathogenic targets for FV require the Kit/SCF signaling pathway in the spleen but not the bone marrow (45). These studies identified the target cells for FV in the spleen and showed that they were present in the spleen megakaryocyte erythroid progenitor (MEP) population originally described by Akashi et al (1).…”

Spi-1 and Fli-1 Directly Activate Common Target Genes Involved in Ribosome Biogenesis in Friend Erythroleukemic Cells

“…During the early stage of the disease, the product of the SFFV env gene, gp55, interacts with the erythropoietin receptor (Epo-R) and constitutively activates signaling pathways allowing the proliferation of proerythroblasts still able to differentiate in the absence of Epo. During this early step, the activation of signaling pathways allowing proerythroblast proliferation is also strictly dependent on the c-Kit receptor and on the small form of the STK receptor tyrosine kinase (20,57). The second stage of the disease is characterized by a clonal population outgrowth of leukemic proerythroblasts blocked in their differentiation and able to grow as permanent cell lines in vitro.…”

Activation of the N-Terminally Truncated Form of the Stk Receptor Tyrosine Kinase Sf-Stk by Friend Virus-Encoded gp55 Is Mediated by Cysteine Residues in the Ecotropic Domain of gp55 and the Extracellular Domain of Sf-Stk

“…These results underscore the possibility that other cellular signals interact with Sf-Stk and Sf-Ron through these cysteines, resulting in the ability of Sf-Stk and Sf-Ron to promote rapid erythroblast expansion. We have shown previously that Friend virus hijacks the BMP4-dependent stress erythropoiesis pathway (55,56). It is therefore plausible that Sf-Stk or Sf-Ron could promote expansive erythropoiesis during times of acute erythropoietic need, and this response could be mediated, in part, by the cysteines in the extracellular domain of Sf-Stk or Sf-Ron with host proteins.…”