Howard J C, Yousefi S, Cheong G, Bernstein A, Ben-David Y
Division of Cancer Research, Sunnybrook Health Science Centre, Toronto, Ontario, Canada.
Oncogene. 1993 Oct;8(10):2721-9.
The erythroleukemias induced by Friend murine leukemia virus (F-MuLV) result from the accumulation of a number of genetic changes, including activation of the Fli-1 proto-oncogene and inactivation of the p53 tumor suppressor gene. We have determined the temporal order of mutation of the genes involved in this multistage malignancy, by serial in vivo transplantation of F-MuLV induced primary erythroleukemias into syngenic Balb/c mice. These primary tumors are capable of growing when transplanted into syngenic mice, but die after several days of in vitro culture. From the transplanted tumors grown in syngenic mice, erythropoietin-dependent cell lines were established in culture that are clonally related to cells in the primary tumors. We show that retroviral insertional activation of the Fli-1 ets family member is the first detectable genetic event in F-MuLV induced primary erythroleukemias. Mutations in the p53 gene were observed in the Epo-dependent cell lines but not in the transplanted erythroleukemias used to establish these cell lines in culture. These data suggest that activation of Fli-1 plays an important role in the early stages of F-MuLV-induced leukemia, perhaps by altering the self-renewal probabilities of erythroid progenitor cells and that p53 mutations immortalize these cells, enabling them to grow in vitro in the presence of Epo.
由弗瑞德氏鼠白血病病毒（F-MuLV）诱导产生的红白血病是多种基因变化积累的结果，这些变化包括Fli-1原癌基因的激活和p53肿瘤抑制基因的失活。我们通过将F-MuLV诱导的原发性红白血病连续体内移植到同基因的Balb/c小鼠中，确定了参与这种多阶段恶性肿瘤形成的基因发生突变的时间顺序。这些原发性肿瘤移植到同基因小鼠中时能够生长，但在体外培养几天后就会死亡。从同基因小鼠体内生长的移植肿瘤中，建立了与原发性肿瘤细胞具有克隆相关性的、依赖促红细胞生成素的细胞系。我们发现，Fli-1 ets家族成员的逆转录病毒插入激活是F-MuLV诱导的原发性红白血病中第一个可检测到的基因事件。在依赖促红细胞生成素的细胞系中观察到了p53基因的突变，但在用于建立这些细胞系的移植红白血病中未观察到。这些数据表明，Fli-1的激活在F-MuLV诱导的白血病早期阶段起着重要作用，可能是通过改变红系祖细胞的自我更新概率，并且p53突变使这些细胞永生化，使其能够在促红细胞生成素存在的情况下在体外生长。
