Grande A, Montanari M, Manfredini R, Tagliafico E, Zanocco-Marani T, Trevisan F, Ligabue G, Siena M, Ferrari S, Ferrari S
Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, Università di Modena e Reggio Emilia, Modena, Italy.
Cell Death Differ. 2001 Jan;8(1):70-82. doi: 10.1038/sj.cdd.4400771.
Although all-trans retinoic acid (ATRA) can restore the differentiation capacity of leukemic promyelocytes, early leukemic myeloblasts are conversely not responsive to ATRA induced granulocytic differentiation. To assess whether this resistance to ATRA is related to an impaired function of the Retinoic Acid Receptor alpha (RARalpha), we performed an analysis of RARalpha expression and transactivation activity, in several myeloid leukemic cell lines, representative of different types of spontaneous acute myeloid leukemias. Our results indicate that a functionally active RARalpha nuclear receptor is expressed in all the analyzed cell lines, regardless of their differentiation capacity following exposure to ATRA. The observation that ATRA treatment is able to induce the expression of retinoic acid target genes, in late- but not in early-myeloblastic leukemic cells, raises the possibility that the differentiation block of these cells is achieved through a chromatin mediated mechanism. Acetylation is apparently not involved in this process, since the histone deacetylase inhibitor trichostatin A, is not able to restore the differentiation capacity of early leukemic myeloblasts. Further investigation is needed to clarify whether myeloid transcription factors, distinct to RARalpha, play a role in the resistance of these cells to ATRA treatment.
尽管全反式维甲酸（ATRA）能够恢复白血病早幼粒细胞的分化能力，但早期白血病髓母细胞却相反，对ATRA诱导的粒细胞分化没有反应。为了评估这种对ATRA的抗性是否与维甲酸受体α（RARα）功能受损有关，我们对几种代表不同类型自发性急性髓性白血病的髓性白血病细胞系进行了RARα表达和反式激活活性分析。我们的结果表明，无论暴露于ATRA后它们的分化能力如何，所有分析的细胞系中均表达有功能活性的RARα核受体。ATRA处理能够在晚期而非早期髓母细胞白血病细胞中诱导维甲酸靶基因表达，这一观察结果增加了这些细胞的分化阻滞是通过染色质介导机制实现的可能性。乙酰化显然不参与此过程，因为组蛋白脱乙酰酶抑制剂曲古抑菌素A无法恢复早期白血病髓母细胞的分化能力。需要进一步研究以阐明不同于RARα的髓系转录因子是否在这些细胞对ATRA治疗的抗性中起作用。
