SPI-1 transforming properties depend upon specifically activated forms of the EPOR

Friend erythroleukemia induced in mice by the spleen focus forming virus (S FFV) is a multi-step process, The pre-leukemic phase of the disease results from the abnormal activation of the Erythropoietin (Epo) receptor by the g p55 env gene product of SFFV, Later in disease progression, the emergence o f leukemic clones is associated with recurrent genetic events, in particula r the activation of the expression of SPI-1, an ETS family transcriptional regulator. We show here that the expression of either SPI-1 or GP55 with th e mouse EPOR in arian primary erythroblasts only marginally affects their n ormal Epo-induced terminal differentiation. In contrast, the co-expression of GP55 and SPI-1 resulted in inhibition of Epo-induced differentiation of EPOR-expressing erythroblasts, promoting instead their proliferation. Co-ex pression of SPI-1 and GP55 also inhibited the apoptotic cell. death program normally induced in response to Epo withdrawal. This cooperation between S PI-1 and GP55 to induce primary erythroblast transformation suggests that p rogression of Friend erythroleukemia critically depends upon inter-dependen t interactions between the molecular events specific of the early and late phase of the disease.