The promyelocytic leukemia-retinoic acid receptor α (PML/RARα) is hypothesized to play a vital role in the pathogenesis of acute promyelocytic leukemia (APL). A previous study has demonstrated that PML/RARα is cleaved by neutrophil elastase (NE) in early myeloid cells, which leads to an increase in the nuclear localization signal (NLS) in RARα and in the incidence of APL. In this study, we explored the effects of NLS-RARα on acute myeloid leukemia (AML) cells and studied the mechanism of its localization. LV-NLS-RARα recombinant lentivirus and negative control LV-NC lentivirus were transfected into HL-60 cells and U937 cells while mutant NLS-RARα were transfected into U937 cells, and all groups were treated with 1α, 25-dihydroxyvitamin D3(1,25D3). The results showed that NLS-RARα was located mainly in the nucleus while mutant NLS-RARα was located in the cytoplasm. Overexpression of NLS-RARα downregulated the expression of CD11b, CD11c, CD14, and three forms of CEBPβ compared to the overexpression of NC and mutant NLS-RARα. It was speculated that the abnormal localization of NLS-RARα was mediated via importin-α/β in the pathogenesis of APL. By producing point mutations in the two NLSs in NLS-RARα, we showed that the nuclear import of NLS-RARα was mainly dependent on the NLS of the RARα portion. Subsequently, we found that importin-α1 (KPNA2)/importin-β1 (KPNB1) participates in the nuclear transport of NLS-RARα. Taken together, abnormal localization of NLS-RARα blocks the differentiation of APL cells, and nuclear localization of NLS-RARα depends on NLS of the RARα portion and is mediated via binding with importin-α/β.

中文翻译：

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NLS-RARα的核输入由输入蛋白α/β介导。

据推测，早幼粒细胞白血病-视黄酸受体α（PML /RARα）在急性早幼粒细胞白血病（APL）的发病机理中起着至关重要的作用。先前的研究表明，PML /RARα在早期髓样细胞中被嗜中性粒细胞弹性蛋白酶（NE）裂解，这导致RARα中的核定位信号（NLS）和APL的发生率增加。在这项研究中，我们探讨了NLS-RARα对急性髓细胞白血病（AML）细胞的影响，并研究了其定位机制。将LV-NLS-RARα重组慢病毒和阴性对照LV-NC慢病毒转染到HL-60细胞和U937细胞中，同时将突变的NLS-RARα转染到U937细胞中，所有组均用1α，25-二羟基维生素D3（1， 25D3）。结果表明，NLS-RARα主要位于细胞核中，而突变型NLS-RARα位于细胞质中。与NC和突变NLS-RARα的过表达相比，NLS-RARα的过表达下调了CD11b，CD11c，CD14和三种CEBPβ的表达。推测在APL的发病过程中，NLS-RARα的异常定位是通过importin-α/β介导的。通过在NLS-RARα中的两个NLS中产生点突变，我们表明NLS-RARα的核输入主要取决于RARα部分的NLS。随后，我们发现importin-α1（KPNA2）/importin-β1（KPNB1）参与了NLS-RARα的核转运。两者合计，NLS-RARα的异常定位会阻止APL细胞的分化，