Strasser A, Harris A W, Bath M L, Cory S
Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia.
Nature. 1990 Nov 22;348(6299):331-3. doi: 10.1038/348331a0.
The putative oncogene bcl-2 is juxtaposed to the immunoglobulin heavy chain (Igh) locus by the t(14;18) chromosomal translocation typical of human follicular B-cell lymphomas. The bcl-2 gene product is not altered by the translocation, but its expression is deregulated, presumably by the Igh enhancer E mu. Constitutive bcl-2 expression seems to augment cell survival, as infection with a bcl-2 retrovirus enables certain growth factor-dependent mouse cell lines to maintain viability when deprived of factor. Furthermore, high levels of the bcl-2 product can protect human B and T lymphoblasts under stress and thereby confer a growth advantage. Mice expressing a bcl-2 transgene controlled by the Igh enhancer accumulate small non-cycling B cells which survive unusually well in vitro but do not show a propensity for spontaneous tumorigenesis. In contrast, an analogous myc transgene, designed to mimic the myc-Igh translocation product typical of Burkitt's lymphoma and rodent plasmacytoma, promotes B lymphoid cell proliferation and predisposes mice to malignancy in pre-B and B lymphoid cells. Previous experiments have suggested that bcl-2 can cooperate with deregulated myc to improve in vitro growth of pre-B and B cells. Here we describe a marked synergy between bcl-2 and myc in doubly transgenic mice. E mu-bcl-2/myc mice show hyperproliferation of pre-B and B cells and develop tumours much faster than E mu-myc mice. Suprisingly, the tumours derive from a cell with the hallmarks of a primitive haemopoietic cell, perhaps a lymphoid-committed stem cell.
推定的癌基因bcl-2通过人滤泡性B细胞淋巴瘤典型的t(14;18)染色体易位与免疫球蛋白重链（Igh）基因座并列。bcl-2基因产物不会因易位而改变，但其表达失调，推测是由Igh增强子Eμ导致的。bcl-2的组成型表达似乎能增强细胞存活能力，因为用bcl-2逆转录病毒感染能使某些依赖生长因子的小鼠细胞系在缺乏因子时维持活力。此外，高水平的bcl-2产物能在应激状态下保护人B和T淋巴母细胞，从而赋予生长优势。表达由Igh增强子控制的bcl-2转基因的小鼠会积累小型非循环B细胞，这些细胞在体外存活能力异常强，但没有自发肿瘤发生的倾向。相比之下，一个类似的myc转基因，设计用于模拟伯基特淋巴瘤和啮齿动物浆细胞瘤典型的myc-Igh易位产物，能促进B淋巴细胞增殖，并使小鼠易患前B和B淋巴细胞恶性肿瘤。先前的实验表明，bcl-2能与失调的myc协同作用，改善前B和B细胞的体外生长。在此我们描述了双转基因小鼠中bcl-2和myc之间显著的协同作用。Eμ-bcl-2/myc小鼠表现出前B和B细胞的过度增殖，并且比Eμ-myc小鼠更快地发生肿瘤。令人惊讶的是，这些肿瘤来源于具有原始造血细胞特征的细胞，可能是一个淋巴样定向干细胞。
