CONSTITUTIVE ACTIVATION OF A VARIANT OF THE ENV-MPL ONCOGENE PRODUCT BY DISULFIDE-LINKED HOMODIMERIZATION

The myeloproliferative leukemia retrovirus (MPLV) has the v-mpl cellul ar sequences transduced in frame with the deleted and rearranged Frien d murine leukemia virus env gene. The resulting env-mpl fusion oncogen e is responsible for an acute myeloproliferative disorder induced in m ice by MPLV. v-mpl is a truncated form of the c-mpl gene which encodes the receptor for thrombopoietin. We investigated the contribution of the Env-Mpl extracellular domain in the constitutive activation of thi s truncated cytokine receptor and found that the rearrangement of the env sequences in the env-mpl fusion gene was not required for oncogeni city. A pathogenic variant, DEL3MPLV, was generated, which differs fro m MPLV by the deletions of 22 amino acids of the Env signal peptide, a ll of the mature Env sequences, and 18 N-terminal amino acids of the v -Mpl extracellular domain, The resulting del3-mpl oncogene product con serves in its extracellular region the first 12 amino acids of the Env signal sequence including a cysteine residue, and 25 amino acids of t he v-Mpl. We show here that a mutation converting this cysteine to a g lycine completely abolishes del3-mpl oncogenicity and that the del3-mp l oncogene product is constitutively activated by disulfide-linked hom odimerization.