Gallagher R E, Said F, Pua I, Papenhausen P R, Paietta E, Wiernik P H
Department of Oncology, Montefiore Medical Center, Bronx, NY 10467.
Leukemia. 1989 Nov;3(11):789-95.
Retinoic acid receptor (RAR)-alpha mRNA expression was studied in a variety of myeloid leukemia cells with variable responsiveness to the induction of terminal differentiation by retinoic acid (RA). Cells from both the wild-type (wt), RA-responsive HL-60 promyelocytic leukemia cell line and a selected greater than or equal to 300-fold RA-resistant subline expressed approximately equal amounts of two RAR-alpha transcripts, 4.0 and 3.1 kb in size. In wt cells, the RAR-alpha did not change during induction of granulocyte differentiation by RA or macrophagic differentiation by 12-0-tetradecanoylphorbol-13-acetate (TPA). Relative to HL-60 cells, other cultured and fresh myeloid leukemia cells expressed 2.5-fold less to equal amounts of the RAR-alpha transcripts. The relative expression in six cases of acute promyelocytic leukemia (APL; two RA-responsive; one, previously treated with 13-cis-RA in vivo, equivocally RA-responsive) and one case of acute myelogenous leukemia (AML) with promyelocytosis (RA unresponsive) was 0.91 +/- 0.14 versus 0.53 +/- 0.14 for eight cases of nonpromyelocytic AML (p congruent to 0.001). Lymphoid leukemia cells expressed 2- to 5-fold less RAR-alpha mRNA. No qualitative variations in the mRNA transcripts were observed, although the 3.1 kb transcript was relatively decreased in three cases. The RAR-alpha gene was not amplified or detectably rearranged in any DNA source, although an apparent EcoRI restriction fragment length polymorphism was observed. It is concluded (a) that the steady-state level of RAR-alpha mRNA is not tightly correlated with natural responsiveness/unresponsiveness or, in some instances, acquired resistance to RA-induced differentiation and (b) that further studies are needed to determine if the mean 1.7-fold higher RAR-alpha mRNA level in APL cells could be an essential factor in the RA-responsiveness of APL cells, as primarily regulated at a different molecular level.
在对维甲酸（RA）诱导终末分化反应各异的多种髓系白血病细胞中，研究了维甲酸受体（RAR）-α mRNA的表达。来自野生型（wt）、对RA有反应的HL-60早幼粒细胞白血病细胞系以及筛选出的对RA耐药性大于或等于300倍的亚系细胞，均表达了大致等量的两种RAR-α转录本，大小分别为4.0 kb和3.1 kb。在wt细胞中，RA诱导粒细胞分化或12-0-十四酰佛波醇-13-乙酸酯（TPA）诱导巨噬细胞分化过程中，RAR-α没有变化。相对于HL-60细胞，其他培养的和新鲜的髓系白血病细胞表达的RAR-α转录本量少2.5倍至等量。6例急性早幼粒细胞白血病（APL；2例对RA有反应；1例曾在体内接受13-顺式RA治疗，对RA反应不明确）和1例伴有早幼粒细胞增多的急性髓性白血病（AML，对RA无反应）中RAR-α的相对表达量为0.91±0.14，而8例非早幼粒细胞性AML中为0.53±0.14（p约等于0.001）。淋巴细胞白血病细胞表达的RAR-α mRNA少2至5倍。尽管在3例中3.1 kb转录本相对减少，但未观察到mRNA转录本的质量变化。在任何DNA来源中，RAR-α基因均未扩增或检测到重排，尽管观察到明显的EcoRI限制性片段长度多态性。得出的结论是：（a）RAR-α mRNA的稳态水平与天然的反应性/无反应性或在某些情况下对RA诱导分化的获得性耐药性没有紧密相关性；（b）需要进一步研究以确定APL细胞中平均高1.7倍的RAR-α mRNA水平是否可能是APL细胞对RA反应性的一个重要因素，因为其主要在不同分子水平上受到调控。
