Rousselot P, Hardas B, Patel A, Guidez F, Gäken J, Castaigne S, Dejean A, de Thé H, Degos L, Farzaneh F
Laboratoire de Biologie Cellulaire Hématopoïétique, Hôpital Saint Louis, Paris, France.
Oncogene. 1994 Feb;9(2):545-51.
Acute promyelocytic leukemia (APL) is characterized by an arrest of granulocytic differentiation and a reciprocal t(15;17) translocation fusing the PML gene to the retinoic acid receptor alpha (RAR alpha) gene. PML was recently identified as a potential transcription factor. In non hematopoietic cells, the transfected PML-RAR alpha product binds all trans retinoic acid and exhibits altered transactivating properties when compared with RAR alpha. A major question raised by these observations is whether PML-RAR alpha contributes to the inhibition of myeloid differentiation. We find that in myeloid cell lines responsive to retinoic acid, PML-RAR alpha blocks retinoic acid mediated transactivation and totally abrogates the retinoic acid mediated granulocytic differentiation. These findings strongly suggest that PML-RAR alpha may, by blocking normal retinoic acid dependent myeloid differentiation, participate in the leukemogenesis of APL. The fact that high doses of all-trans retinoic acid relieve the inhibitory effect of PML-RAR alpha corroborates the therapeutic effect of all-trans retinoic acid in APL patients.
急性早幼粒细胞白血病（APL）的特征是粒细胞分化停滞以及15号和17号染色体相互易位，导致早幼粒细胞白血病（PML）基因与维甲酸受体α（RARα）基因融合。PML最近被鉴定为一种潜在的转录因子。在非造血细胞中，转染后的PML-RARα产物与全反式维甲酸结合，与RARα相比，其反式激活特性发生改变。这些观察结果提出的一个主要问题是，PML-RARα是否有助于抑制髓系分化。我们发现，在对维甲酸有反应的髓系细胞系中，PML-RARα阻断维甲酸介导的反式激活，并完全消除维甲酸介导的粒细胞分化。这些发现强烈表明，PML-RARα可能通过阻断正常的维甲酸依赖性髓系分化，参与APL的白血病发生。高剂量全反式维甲酸可减轻PML-RARα的抑制作用，这一事实证实了全反式维甲酸对APL患者的治疗效果。
