A mutated PML/RARA found in the retinoid maturation resistant NB4 subclone, NB4-R2, blocks RARA and wild-type PML/RARA transcriptional activities
A mutated PML/RARA found in the retinoid maturation resistant NB4 subclone, NB4-R2, blocks RARA and wild-type PML/RARA transcriptional activities
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DOI：
10.1038/sj.leu.2401683
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发表时间：
2000-02-01
期刊：
影响因子：
11.4
通讯作者：
Lanotte, M
中科院分区：
文献类型：
--
作者：
Duprez, E;Benoit, G;Lanotte, M
与急性早幼粒细胞白血病相关的融合蛋白PML/RARA表现为具有改变的反式激活性质的异常视黄酸（RA）受体，但仍可被RA诱导。嵌合蛋白被认为促进白血病发生，但也矛盾地介导APL细胞对ATRA的敏感性。这已经得到了文献的支持，文献报道体外ATRA抗性的特征在于PML/RARA的RARA/E结构域的缺陷。在本报告中，我们确定了PML/RARA的E结构域中的一个新突变，该突变与NB 4细胞的RA耐药亚系NB 4-R2相关。该突变与HL 60-R中发现的GIn 411突变相同，将氨基酸GIn 903改变为同相终止密码子，产生截短形式的PML/RARA，其C末端缺失52个氨基酸。我们研究了截短的PML/RARA蛋白对PML NE形成和RARA以及PML/RARA转录活性的影响。我们在这里表明，融合突变体对野生型PML，PML/RARA和RARA转录活性产生显性负效应。这些发现突出了PML/RARA的RARA E结构域在介导APL细胞中的RA敏感性中的重要作用。
The fusion protein PML/RARA, associated with acute promyelocytic leukemia behaves as an abnormal retinoic acid (RA) receptor with altered transactivation properties but is still inducible by RA. The chimeric protein is thought to promote leukemogenesis but also paradoxically to mediate the sensitivity to ATRA of APL cells. This has been supported by works reporting that in vitro ATRA resistance is characterized by defects in the RARA/E-domain of PML/RARA. In the present report, we identified a new mutation in the E domain of PML/RARA which is associated with a RA-resistant subline of NB4 cells; NB4-R2. This mutation, identical to the GIn411 mutation found in HL60-R, changes the amino acid GIn903 to an in-phase stop codon, generating a truncated form of PML/RARA which has lost 52 amino acids at its C-terminal end. We have studied the effect of the truncated PML/RARA protein on PML NE formation and RARA and PML/RARA transcriptional activity. We show here that the fusion mutant exerts a dominant negative effect on wild-type PML, PML/RARA and RARA transcription activity. These findings highlight the important role of the RARA E-domain of PML/RARA in mediating RA sensitivity in APL cells.