Chomienne C, Balitrand N, Ballerini P, Castaigne S, de Thé H, Degos L
Laboratoire de Biologie Cellulaire Hématopoïétique, Hôpital Saint Louis, Paris, France.
J Clin Invest. 1991 Dec;88(6):2150-4. doi: 10.1172/JCI115547.
We have recently demonstrated that all-trans retinoic acid (RA), the active metabolite of vitamin A, is an efficient alternative to chemotherapy in the treatment of acute promyelocytic leukemia (AML3). We have further shown that, in these AML3 cells, the gene of the retinoic acid receptor-alpha (RAR alpha) is translocated from chromosome 17 to chromosome 15, and fused to a new gene, PLM. This results in the expression of both normal and chimeric RAR alpha transcripts in AML3 cells. The PLM-RAR alpha protein may account for the impairment of differentiation and thus leukemogenesis, but not for the paradoxical efficacy of RA in these cells. In an attempt to elucidate RA's differentiative effect in AML3 patients, the present work examined the in vitro and in vivo modulation of the normal RAR alpha transcripts by all-trans RA in seven cases of AML3. In all samples, Northern blot analysis revealed a low expression of the two normal RAR alpha transcripts compared with other human myeloid leukemic cells. No modulation was observed after 4-8 d of in vivo therapy with all-trans RA 45 mg/m2 per d. In vitro incubation with all-trans RA, however, increased the level of expression of the normal RAR alpha transcripts in AML3 cells but not in other AML leukemic subtypes. This modulation of the two normal RAR alpha transcripts appeared to be an early and primary event of RA's differentiating effect. We therefore suggest that up-regulation of the normal RAR alpha gene expression by pharmacological concentrations of all-trans RA may restore the normal differentiation pathway in these cells.
我们最近证实，维生素A的活性代谢产物全反式维甲酸（RA）是治疗急性早幼粒细胞白血病（AML3）的一种有效替代化疗方法。我们还进一步表明，在这些AML3细胞中，维甲酸受体α（RARα）基因从17号染色体易位至15号染色体，并与一个新基因PLM融合。这导致AML3细胞中正常和嵌合RARα转录本均得以表达。PLM-RARα蛋白可能是导致分化受损从而引发白血病的原因，但并非RA在这些细胞中产生矛盾疗效的原因。为了阐明RA对AML3患者的分化作用，本研究检测了全反式RA对7例AML3患者正常RARα转录本的体外和体内调节情况。在所有样本中，Northern印迹分析显示，与其他人类髓系白血病细胞相比，两种正常RARα转录本的表达水平较低。每天给予45mg/m2全反式RA进行4至8天的体内治疗后，未观察到调节作用。然而，在体外与全反式RA孵育后，AML3细胞中正常RARα转录本的表达水平升高，而其他AML白血病亚型则未出现这种情况。这两种正常RARα转录本的调节似乎是RA分化作用的早期和主要事件。因此，我们认为，药理学浓度的全反式RA上调正常RARα基因表达可能会恢复这些细胞中的正常分化途径。
