Nigten J, Breems-de Ridder M C, Erpelinck-Verschueren C A J, Nikoloski G, van der Reijden B A, van Wageningen S, van Hennik P B, de Witte T, Löwenberg B, Jansen J H
Central Hematology Laboratory and Department of Hematology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Leukemia. 2005 May;19(5):799-805. doi: 10.1038/sj.leu.2403699.
Acute promyelocytic leukemia (APL) is uniquely sensitive to treatment with all-trans retinoic acid (ATRA), which results in the expression of genes that induce the terminal granulocytic differentiation of the leukemic blasts. Here we report the identification of two ATRA responsive genes in APL cells, ID1 and ID2. These proteins act as antagonists of basic helix-loop-helix (bHLH) transcription factors. ATRA induced a rapid increase in ID1 and ID2, both in the APL cell line NB4 as well as in primary patient cells. In addition, a strong downregulation of E2A was observed. E2A acts as a general heterodimerization partner for many bHLH proteins that are involved in differentiation control in various tissues. The simultaneous upregulation of ID1 and ID2, and the downregulation of E2A suggest a role for bHLH proteins in the induction of differentiation of APL cells following ATRA treatment. To test the relevance of this upregulation, ID1 and ID2 were overexpressed in NB4 cells. Overexpression inhibited proliferation and induced a G0/G1 accumulation. These results indicate that ID1 and ID2 are important retinoic acid responsive genes in APL, and suggest that the inhibition of specific bHLH transcription factor complexes may play a role in the therapeutic effect of ATRA in APL.
急性早幼粒细胞白血病（APL）对全反式维甲酸（ATRA）治疗具有独特的敏感性，这会导致诱导白血病母细胞终末粒细胞分化的基因表达。在此我们报告在APL细胞中鉴定出两个ATRA反应基因，即ID1和ID2。这些蛋白质作为碱性螺旋-环-螺旋（bHLH）转录因子的拮抗剂。ATRA在APL细胞系NB4以及原发性患者细胞中均诱导ID1和ID2迅速增加。此外，还观察到E2A的强烈下调。E2A作为许多参与各种组织分化控制的bHLH蛋白的通用异源二聚化伴侣。ID1和ID2的同时上调以及E2A的下调表明bHLH蛋白在ATRA治疗后APL细胞分化诱导中发挥作用。为了测试这种上调的相关性，在NB4细胞中过表达ID1和ID2。过表达抑制增殖并诱导G0/G1期积累。这些结果表明ID1和ID2是APL中重要的视黄酸反应基因，并提示抑制特定的bHLH转录因子复合物可能在ATRA对APL的治疗作用中发挥作用。
