Lehmann S, Paul C, Törmä H
Department of Hematology, Karolinska Institute, Huddinge Hospital, Stockholm, Sweden.
Clin Cancer Res. 2001 Feb;7(2):367-73.
All-trans-retinoic acid (ATRA) has significantly improved the treatment results in acute promyelocytic leukemia (M3). In non-M3 acute myeloid leukemia (AML), the effects are less clear, and there is a pronounced heterogeneity in the sensitivity to the growth-inhibitory effects of retinoids in leukemic cells from different non-M3 AML patients. Retinoids exert their effects through a number of nuclear receptors [retinoic acid receptors (RARs) and retinoid X receptors (RXRs)]. In this study, we determined the expression of RAR alpha, RAR beta, RAR gamma, and RXR alpha by real-time PCR in four cell lines and in blast cells from patients with non-M3 AML before and after ATRA incubation. All four receptors were expressed in cells from all 18 tested patient samples and in four myeloid cell lines. In the majority of the patient samples as well as in the cell lines, there was a pattern of high expression of RAR alpha and RXR alpha and low expression of RAR beta and RAR gamma. There was no correlation between the basal expression of any of the retinoid receptors and sensitivity to ATRA. A 24-h exposure to ATRA increased the expression of RAR alpha, RAR beta, RAR gamma, and RXR alpha in 46%, 77%, 30%, and 38% of the samples, respectively. The mean increase in receptor expression was most pronounced for RAR beta and RXR alpha. There was a significant correlation between an increase in RAR beta expression in response to ATRA and sensitivity to ATRA (P < 0.014). No such correlations were found for RAR alpha, RAR gamma, and RXR alpha. The expression of the monocytoid marker CD14 was significantly correlated with increased expression of RAR alpha (P = 0.03). We conclude that RAR alpha, RAR beta, RAR gamma, and RXR alpha are expressed in non-M3 AML blast cells and that ATRA-induced expression of RAR beta may be a marker for retinoid sensitivity.
全反式维甲酸（ATRA）显著改善了急性早幼粒细胞白血病（M3）的治疗效果。在非M3型急性髓系白血病（AML）中，其效果尚不清楚，并且来自不同非M3型AML患者的白血病细胞对维甲酸生长抑制作用的敏感性存在明显异质性。维甲酸通过多种核受体[维甲酸受体（RARs）和维甲酸X受体（RXRs）]发挥作用。在本研究中，我们通过实时PCR测定了四种细胞系以及非M3型AML患者的原始细胞在ATRA孵育前后RARα、RARβ、RARγ和RXRα的表达。所有四种受体在所有18个测试患者样本的细胞以及四种髓系细胞系中均有表达。在大多数患者样本以及细胞系中，存在RARα和RXRα高表达、RARβ和RARγ低表达的模式。任何一种维甲酸受体的基础表达与对ATRA的敏感性之间均无相关性。24小时暴露于ATRA后，分别有46%、77%、30%和38%的样本中RARα、RARβ、RARγ和RXRα的表达增加。受体表达的平均增加在RARβ和RXRα中最为明显。ATRA诱导的RARβ表达增加与对ATRA的敏感性之间存在显著相关性（P < 0.014）。RARα、RARγ和RXRα未发现此类相关性。单核细胞标志物CD14的表达与RARα表达增加显著相关（P = 0.03）。我们得出结论，RARα、RARβ、RARγ和RXRα在非M3型AML原始细胞中表达，并且ATRA诱导的RARβ表达可能是维甲酸敏感性的标志物。
