Nason-Burchenal K, Gandini D, Botto M, Allopenna J, Seale J R, Cross N C, Goldman J M, Dmitrovsky E, Pandolfi P P
Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Blood. 1996 Nov 15;88(10):3926-36.
The PML gene is fused to the retinoic acid receptor alpha gene (RAR alpha) in the acute promyelocytic leukemia (APL) 15; 17 translocation. PML is expressed in diverse tissues and cell lines and localized in the nucleus with a typical speckled pattern. In the bone marrow, it is preferentially expressed in myeloid cells. PML appears to be transcriptionally regulated by class I and II interferons, which raises the possibility that interferons modulate the function and growth and differentiation potential of normal myeloid cells and precursors by activating PML-dependent pathways. Similarly, interferons could act on APL cells, alone or in combination with all-trans retinoic acid (RA), especially if the PML/RAR alpha fusion transcript that results from the t(15; 17) is induced by interferon. We report here that PML is expressed at low levels or not expressed in normal circulating human monocytes, lymphocytes, and polymorphonucleate cells, but is markedly induced by interferon; that PML and PML/RAR alpha expression is augmented by interferon in the NB4 APL cell line, which carries the t(15; 17), and in APL blasts from patients; that interferon inhibits growth and survival of NB4 APL cells in cooperation with RA; that interferons alone have minimal maturation effect on NB4 cells; and, finally, that interferon gamma, but not alpha or beta, induces maturation and growth suppression of NB4 cells with de novo retinoid resistance, and partially restores RA response.
在急性早幼粒细胞白血病（APL）的15；17易位中，早幼粒细胞白血病（PML）基因与维甲酸受体α基因（RARα）融合。PML在多种组织和细胞系中表达，定位于细胞核，呈典型的斑点状模式。在骨髓中，它优先在髓系细胞中表达。PML似乎受I类和II类干扰素的转录调控，这增加了干扰素通过激活PML依赖途径调节正常髓系细胞及其前体细胞的功能、生长和分化潜能的可能性。同样，干扰素可单独或与全反式维甲酸（RA）联合作用于APL细胞，特别是如果由t（15；17）产生的PML/RARα融合转录本由干扰素诱导。我们在此报告，PML在正常循环的人单核细胞、淋巴细胞和多形核细胞中低水平表达或不表达，但可被干扰素显著诱导；在携带t（15；17）的NB4 APL细胞系以及患者的APL原始细胞中，干扰素可增强PML和PML/RARα的表达；干扰素与RA协同抑制NB4 APL细胞的生长和存活；单独使用干扰素对NB4细胞的成熟作用最小；最后，γ干扰素而非α或β干扰素可诱导对维甲酸耐药的NB4细胞成熟并抑制其生长，并部分恢复其对RA的反应。
