Inaba T, Inukai T, Yoshihara T, Seyschab H, Ashmun R A, Canman C E, Laken S J, Kastan M B, Look A T
Department of Experimental Oncology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Nature. 1996 Aug 8;382(6591):541-4. doi: 10.1038/382541a0.
The E2A-HLF (for hepatic leukaemia factor) fusion gene, formed by action of the t(17;19) (q22;p13) chromosomal translocation, drives the leukaemic transformation of early B-cell precursors, but the mechanism of this activity remains unknown. Here we report that human leukaemia cells carrying the translocation t(17;19) rapidly died by apoptosis when programmed to express a dominant-negative suppressor of the fusion protein E2A-HLF, indicating that the chimaeric oncoprotein probably affects cell survival rather than cell growth. Moreover, when introduced into murine pro-B lymphocytes, the oncogenic E2A-HLF fusion protein reversed both interleukin-3-dependent and p53-mediated apoptosis. The close homology of the basic region/leucine zipper (bZIP) DNA-binding and dimerization domain of HLF to that of the CES-2 cell-death specification protein of Caenorhabditis elegans suggests a model of leukaemogenesis in which E2A-HLF blocks an early step within an evolutionarily conserved cell-death pathway.
由t(17;19)(q22;p13)染色体易位作用形成的E2A-HLF（肝白血病因子）融合基因驱动早期B细胞前体的白血病转化，但其这种活性的机制仍不清楚。我们在此报告，携带t(17;19)易位的人类白血病细胞在被编程表达融合蛋白E2A-HLF的显性负性抑制因子时会迅速通过凋亡死亡，这表明嵌合致癌蛋白可能影响细胞存活而非细胞生长。此外，当致癌性E2A-HLF融合蛋白被导入小鼠前B淋巴细胞时，它逆转了白细胞介素-3依赖性凋亡和p53介导的凋亡。HLF的碱性区域/亮氨酸拉链（bZIP）DNA结合和二聚化结构域与秀丽隐杆线虫的CES-2细胞死亡特异性蛋白的该结构域高度同源，这提示了一种白血病发生模型，即E2A-HLF阻断了进化保守的细胞死亡途径中的早期步骤。
