Grisolano J L, Wesselschmidt R L, Pelicci P G, Ley T J
Department of Internal Medicine, Washington University Medical School, St Louis, MO 63110, USA.
Blood. 1997 Jan 15;89(2):376-87.
Acute promyelocytic leukemia (APML) is characterized by abnormal myeloid development, resulting an accumulation of leukemic promyelocytes that are often highly sensitive to retinoic acid. A balanced t(15;17) (q22;q21) reciprocal chromosomal translocation is found in approximately 90% of APML patients; this translocation fuses the PML gene on chromosome 15 to the retinoic acid receptor alpha (RAR alpha) gene on chromosome 17, creating two novel fusion genes, PML-RAR alpha and RAR alpha-PML. The PML-RAR alpha fusion gene product, which is expressed in virtually all patients with t(15;17), is thought to play a direct role in the pathogenesis of APML. To determine whether PML-RAR alpha is sufficient to cause APML in an animal model, we used the promyelocyte-specific targeting sequences of the human cathepsin G (hCG) gene to direct the expression of a PML-RAR alpha cDNA to the early myeloid cells of transgenic mice. Mice expressing the hCG-PML-RAR alpha transgene were found to have altered myeloid development that was characterized by increased percentages of immature and mature myeloid cells in the peripheral blood, bone marrow, and spleen. In addition, approximately 30% of transgene-expressing mice eventually developed acute myeloid leukemia after a long latent period. The splenic promyelocytes of mice with both the nonleukemic and leukemic phenotypes responded to all-trans retinoic acid (ATRA) treatment, which caused apoptosis of myeloid precursors. Although low-level expression of the hCG-PML-RAR alpha transgene is not sufficient to directly cause acute myeloid leukemia in mice, its expression alters myeloid development, resulting in an accumulation of myeloid precursors that may be susceptible to cooperative transforming events.
急性早幼粒细胞白血病（APML）的特征是髓系发育异常，导致白血病早幼粒细胞积聚，这些细胞通常对维甲酸高度敏感。在大约90%的APML患者中发现了平衡的t(15;17) (q22;q21) 相互染色体易位；这种易位将15号染色体上的PML基因与17号染色体上的维甲酸受体α（RARα）基因融合，产生两个新的融合基因，PML-RARα和RARα-PML。几乎所有t(15;17)患者都表达PML-RARα融合基因产物，该产物被认为在APML的发病机制中起直接作用。为了确定PML-RARα在动物模型中是否足以引发APML，我们使用人组织蛋白酶G（hCG）基因的早幼粒细胞特异性靶向序列，将PML-RARα cDNA的表达导向转基因小鼠的早期髓系细胞。发现表达hCG-PML-RARα转基因的小鼠髓系发育发生改变，其特征是外周血、骨髓和脾脏中未成熟和成熟髓系细胞的百分比增加。此外，大约30%表达转基因的小鼠在长时间潜伏期后最终发展为急性髓系白血病。具有非白血病和白血病表型的小鼠的脾脏早幼粒细胞对全反式维甲酸（ATRA）治疗有反应，这导致髓系前体细胞凋亡。虽然hCG-PML-RARα转基因的低水平表达不足以直接在小鼠中引发急性髓系白血病，但其表达改变了髓系发育，导致髓系前体细胞积聚，这些细胞可能易受协同转化事件的影响。
