NOVEL PRIMITIVE LYMPHOID TUMORS INDUCED IN TRANSGENIC MICE BY COOPERATION BETWEEN MYC AND BCL-2
NOVEL PRIMITIVE LYMPHOID TUMORS INDUCED IN TRANSGENIC MICE BY COOPERATION BETWEEN MYC AND BCL-2
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DOI：
10.1038/348331a0
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发表时间：
1990-11-22
期刊：
影响因子：
64.8
通讯作者：
CORY, S
中科院分区：
文献类型：
--
作者：
STRASSER, A;HARRIS, AW;CORY, S
假定的癌基因bcl-2通过人类滤泡B细胞淋巴瘤典型的t（14;18）染色体易位4与免疫球蛋白重链（Igh）位点1 - 3并列。bcl-2基因产物（参考文献5，6）不因易位而改变，但其表达被解除调节6 -8，推测是由Igh增强子Eµ引起的。组成性bcl-2表达似乎增加细胞存活，因为用bcl-2逆转录病毒感染使某些生长因子依赖性小鼠细胞系在缺乏因子时保持活力9，10。此外，高水平的bcl-2产物可以在应激下保护人B和T淋巴母细胞11，12，从而赋予生长潜能12 -14。表达由Igh增强子控制的abcl-2转基因的小鼠积累了小的非循环B细胞，这些细胞在体外存活得非常韦林15 - 17，但没有显示出自发性肿瘤发生的倾向15，16。相反，设计成模拟伯基特淋巴瘤和啮齿动物浆细胞瘤典型的myc-Ig易位产物的类似myc转基因18促进B淋巴细胞增殖，并使小鼠在前B和B淋巴细胞中易患恶性肿瘤19 -22。先前的实验表明bcl-2可以与去调节的myc协同作用以改善前B和B细胞的体外生长9，11。在此我们描述了bcl-2和mycin双转基因小鼠之间的显著协同作用。Eµ-bcl-2/mycmice表现出前B和B细胞的过度增殖，并且比Eµ-mycmice发展肿瘤更快。令人惊讶的是，这些肿瘤源自一种具有原始造血细胞特征的细胞，可能是一种淋巴定向干细胞。
THE putative oncogenebcl-2 is juxtaposed to the immunoglobulin heavy chain (Igh) locus1-3by the t(14;18) chromosomal translocation typical of human follicular B-cell lymphomas4. Thebcl-2 gene product (refs 5,6) is not altered by the translocation, but its expression is deregulated6–8, presumably by theIghenhancer Eµ. Constitutivebcl-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 factor9,10. Furthermore, high levels of thebcl-2 product can protect human B and T lymphoblasts under stress11,12and thereby confer a growth advantage12–14. Mice expressing abcl-2 transgene controlled by theIghenhancer accumulate small non-cycling B cells which survive unusually wellin vitro15–17but do not show a propensity for spontaneous tumorigenesis15,16. In contrast, an analogousmyctransgene, designed to mimic themyc–Ightranslocation product typical of Burkitt's lymphoma and rodent plasmacytoma18, promotes B lymphoid cell proliferation and predisposes mice to malignancy in pre-B and B lymphoid cells19-22. Previous experiments have suggested thatbcl-2 can cooperate with deregulatedmycto improvein vitrogrowth of pre-B and B cells9,11. Here we describe a marked synergy betweenbcl-2 andmycin doubly transgenic mice. Eµ–bcl–2/mycmice show hyperproliferation of pre-B and B cells and develop tumours much faster than Eµ–mycmice. Surprisingly, the tumours derive from a cell with the hallmarks of a primitive haemopoietic cell, perhaps a lymphoid-committed stem cell.