de Parseval N, Bordereaux D, Varlet P, Gisselbrecht S, Sola B
Hopital Cochin, Institut Cochin de Genetique Moleculaire, U-363 Institut National de la Santé et de la Recherche Médicale, Université Paris V, France.
J Virol. 1995 Jun;69(6):3597-604. doi: 10.1128/JVI.69.6.3597-3604.1995.
The c-fms gene encodes the receptor for the macrophage colony-stimulating factor, which plays a key role in the proliferation and differentiation of cells of the myelomonocytic lineage. In order to study the effects of overexpression of the macrophage colony-stimulating factor receptor in hematopoietic cells, a Harvey sarcoma virus-derived retroviral vector containing the murine c-fms cDNA was pseudotyped with Friend murine leukemia virus and inoculated into newborn DBA/2 mice. This viral complex induced monoclonal or oligoclonal leukemias with a shorter latency than that for Friend murine leukemia virus alone. Unexpectedly, 60% of the integrated fms proviruses had deletions at the 5' end of the c-fms gene. Sequence analysis of seven mutant proviruses indicated that the deletions always included the c-fms ligand binding domain and either occurred within the c-fms sequences, leaving the fms open reading frame unchanged, or joined VL30 sequences located at the 5' end of the parental retroviral vector to internal c-fms sequences, resulting in truncated fms proteins devoid of the canonical signal peptide. In contrast to all tyrosine kinase receptors transduced in retroviruses, no helper gag- or env-derived sequences were fused to the rearranged fms sequences. Viral supernatants isolated from hematopoietic tumors with viruses with deletions were able to transform NIH 3T3 cells as efficiently as parental fms virus, indicating that deletions resulted in constitutive activation of the c-fms gene. These oncogenic variants differ from those transduced in the Suzan McDonough strain of feline sarcoma 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 rearrangement and its relevance in the occurrence of hematopoietic tumors are discussed.
c-fms基因编码巨噬细胞集落刺激因子的受体，该受体在骨髓单核细胞系细胞的增殖和分化中起关键作用。为了研究巨噬细胞集落刺激因子受体在造血细胞中过表达的影响，将含有鼠源c-fms cDNA的哈维肉瘤病毒衍生逆转录病毒载体用弗氏鼠白血病病毒进行假型包装，并接种到新生的DBA/2小鼠体内。这种病毒复合物诱导产生单克隆或寡克隆白血病，其潜伏期比单独使用弗氏鼠白血病病毒时更短。出乎意料的是，60%整合的fms前病毒在c-fms基因的5'端存在缺失。对七个突变前病毒的序列分析表明，缺失总是包括c-fms配体结合结构域，要么发生在c-fms序列内，使fms开放阅读框不变，要么将位于亲本逆转录病毒载体5'端的VL30序列与c-fms内部序列连接，导致产生缺乏典型信号肽的截短fms蛋白。与逆转录病毒转导的所有酪氨酸激酶受体不同，没有辅助gag或env衍生序列与重排的fms序列融合。从带有缺失的病毒的造血肿瘤中分离出的病毒上清液能够像亲本fms病毒一样有效地转化NIH 3T3细胞，这表明缺失导致c-fms基因的组成性激活。这些致癌变体与在猫肉瘤病毒的苏珊·麦克多诺株中转导的变体不同（L. 唐纳、L. A. 费德勒、C. F. 加龙、S. J. 安德森和C. J. 谢尔，《病毒学杂志》41:489 - 500，1982年）。讨论了c-fms重排的高发生率及其在造血肿瘤发生中的相关性。
