A speculative model of multistage Friend disease resulting from an interaction of the EpoR and SF-Stk.

(A) In the first stage of the disease, an SFFV provirus integrates into the host genome and encodes the oncogenic envelope protein, gp55. Then, gp55 forms a high-molecular-weight complex with the EpoR and perhaps SF-Stk, both at the cell surface and within an intracellular compartment. This binding interaction leads to the constitutive activation of the EpoR. SF-Stk may contribute to this mechanism in one or more ways. For instance, SF-Stk may increase the affinity of EpoR-gp55 interaction, increase the expression of cell surface EpoR, act as a coreceptor that activates additional downstream signaling events, or activate unique downstream signaling events that are required for erythroblast transformation. (B) In the second stage of the disease, proviral integrations cause up-regulation of Sfpi1/PU.1 expression and inactivation of wild-type p53 as well as other events (not shown).101 These mutations confer a selective advantage. Although this remains speculative, Sfpi1/PU.1 may activate SF-Stk as well as other target genes, resulting in progression toward erythroleukemia.