ISOLATION OF NEW ONCOGENIC FORMS OF THE MURINE C-FMS GENE

The c-fms gene encodes the receptor for the macrophage colony-stimulat ing factor, which plays a key role in the proliferation and differenti ation of cells of the myelomonocytic lineage, In order to study the ef fects of overexpression of the macrophage colony-stimulating factor re ceptor in hematopoietic cells, a Harvey sarcoma virus-derived retrovir al vector containing the murine c-fms cDNA was pseudotyped with Friend murine leukemia virus and inoculated into newborn DBA/2 mice. This vi ral complex induced monoclonal or oligoclonal leukemias with a shorter latency than that for Friend murine leukemia virus alone, Unexpectedl y, 60% of the integrated fins proviruses had deletions at the 5' end o f the c-fms gene. Sequence analysis of seven mutant proviruses indicat ed that the deletions always included the c-fms ligand binding domain and either occurred within the c-fms sequences, leaving the fms open r eading frame unchanged, or joined VL30 sequences located at the 5' end of the parental retroviral vector to internal c-fms sequences, result ing in truncated fms proteins devoid of the canonical signal peptide. In contrast to all tyrosine kinase receptors transduced in retroviruse s, no helper gag- or env-derived sequences were fused to the rearrange d fms sequences. Viral supernatants isolated from hematopoietic tumors with viruses with deletions were able to transform NIH 3T3 cells as e fficiently as parental fms virus, indicating that deletions resulted i n constitutive activation of the c-fms gene. These oncogenic variants differ from those transduced in the Suzan McDonough strain of feline s arcoma viruses (L. Donner, L. A. Fedele, C. F. Garon, S. J. Anderson, and C. J. Sherr, J. Virol, 41:489-500, 1982). The high rate of c-fms r earrangement and its relevance in the occurrence of hematopoietic tumo rs are discussed.