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.

The characteristic progression and specificity of Friend virus for the erythroid lineage have allowed for the identification of a number of host-encoded loci that are required for disease progression. Several of these loci, including the Friend virus susceptibility gene 2 (Fv2), dominant white spotting gene (W), and Steel gene (Sl), regulate the initial polyclonal expansion of infected erythroid progenitor cells. W and Sl encode the Kit receptor tyrosine kinase and its ligand, stem cell factor, respectively. W mutant mice are severely anemic, and earlier work suggested that this defect in erythroid differentiation is the cause for the resistance to Friend virus-induced erythroleukemia. Here we show that in bone marrow, W/W(v) mice have near normal numbers of target cells and the initial infection of bone marrow occurs normally in vivo. In contrast, spleen cells from W/W(v) mice infected both in vitro and in vivo with Friend virus failed to give rise to erythropoietin-independent colonies at any time following Friend virus infection, suggesting that mutation of the Kit receptor specifically affects target cells in the spleen, rendering the mutant mice resistant to the development of Friend virus-induced erythroleukemia. In addition, we show that the Kit+ pathogenic targets of Friend virus in the spleen are distinct from the pathogenic targets in bone marrow and this population of spleen target cells is markedly decreased in W/W(v) mice and these cells fail to express Sf-Stk. These results also underscore the unique nature of the spleen microenvironment in its role in supporting the progression of acute leukemia in Friend virus-infected mice.

Macrophage-stimulating protein cooperates with erythropoietin to induce colony formation and MAP kinase activation in primary erythroid progenitor cells.

We have shown that Fv2, the Friend virus susceptibility 2 locus, encodes a naturally occurring amino-terminally truncated form of the STK receptor tyrosine kinase (Sf-Stk). Sf-Stk appears to interact with the viral glycoprotein gp55 and drive erythropoietin (Epo)-independent expansion of Friend virus-infected erythroblasts. Presumably, Sf-Stk provides signals that cooperate with EpoR signaling to induce the polyclonal expansion of infected cells. In this report, we show that macrophage-stimulating protein (MSP), the ligand for full-length STK, can also cooperate with Epo to enhance burst-forming units-erythroid (BFU-E) formation. To evaluate the signals induced by MSP/STK in primary erythroid progenitor cells, we adapted a method for the expansion of murine bone marrow mononuclear cells. The expanded progenitor cells express STK and respond to MSP in a colony assay. Furthermore, we demonstrate that low doses of MSP and Epo stimulation of the expanded cells cooperate to induce the phosphorylation of MAP kinase. Using the MEK inhibitor PD98059, we show that the activation of ERK is required for the enhanced BFU-E formation in response to MSP. These findings suggest that MSP has the ability to enhance erythroid colony formation in response to Epo, and that this response is dependent on the ability of MSP to induce the MAP kinase pathway.