Fagioli M, Grignani F, Ferrucci P F, Alcalay M, Mencarelli A, Nicoletti I, Grignani F, Pelicci P G
Istituto Clinica medica I, Università degli Studi Perugia, Policlinico Monteluce, Italy.
Leukemia. 1994 Apr;8 Suppl 1:S7-11.
Acute promyelocytic leukaemia is characterized by an expansion of haematopoietic precursors arrested at the promyelocytic stage (1). The differentiation block can be reversed by retinoic acid, which induces blast differentiation both in vitro (2) and in vivo (3-4). Acute promyelocytic leukaemia is also characterized by a 15;17 chromosome translocation (5) with breakpoints within the retinoic acid alpha receptor (RAR alpha) gene on 17 and within the PML gene, that encodes a putative transcription factor of unknown function (6-7), on 15 (8-10). As a consequence of the translocation a PML/RAR alpha gene is formed. It is transcriptionally active and encodes a PML/RAR alpha fusion protein detectable in all APL cases (11-14). We expressed the PML/RAR alpha protein in U937 myeloid precursor cell line and show that they: 1) lose the capacity to differentiate under the action of different stimuli (vitamin D3, transforming growth factor beta 1); ii) acquire enhanced sensitivity to retinoic acid; iii) exhibit a higher growth rate that is due to a reduction in apoptotic cell death. These results provide the first evidence of biological activity of PML/RAR alpha and recapitulate critical features of the promyelocytic leukemia phenotype.
急性早幼粒细胞白血病的特征是处于早幼粒细胞阶段的造血前体细胞扩增（1）。维甲酸可逆转这种分化阻滞，它在体外（2）和体内（3 - 4）均可诱导原始细胞分化。急性早幼粒细胞白血病还具有15;17染色体易位的特征（5），其断点位于17号染色体上的维甲酸α受体（RARα）基因内以及15号染色体上的PML基因内，PML基因编码一种功能未知的假定转录因子（6 - 7）（8 - 10）。由于这种易位，形成了PML/RARα基因。它具有转录活性，编码一种在所有急性早幼粒细胞白血病病例中均可检测到的PML/RARα融合蛋白（11 - 14）。我们在U937髓系前体细胞系中表达了PML/RARα蛋白，并表明它们：1）在不同刺激（维生素D3、转化生长因子β1）作用下失去分化能力；ii）对维甲酸的敏感性增强；iii）由于凋亡细胞死亡减少而表现出更高的生长速率。这些结果提供了PML/RARα生物活性的首个证据，并概括了早幼粒细胞白血病表型的关键特征。
