A majority of acute promyelocytic leukaemia (APL) cases are characterized by the PML-RARα fusion gene. Previous studies have shown that neutrophil elastase (NE) can cleave PML-RARα and is important for the development of APL. Here, we demonstrate that one of the cleavage products of PML-RARα, NLS-RARα, can block cell differentiation by repressing the expression of the target genes within the retinoic acid signalling pathway. The results of reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot analysis showed that NLS-RARα depressed the expression of the cell differentiation marker protein, CD11b and CEBPβ, as well as the retinoic acid signalling pathway target genes, RARβ and CEBPε. Studies have shown that NLS-RARα forms heterodimers with retinoid X receptor α(RXRα) and interacts with SMRT. When treated with all-trans retinoic acid (ATRA), NLS-RARα exhibits diminished transcriptional activity compared to RARα. Moreover, in the presence of high doses of ATRA, NLS-RARα could be degraded along with the consequent transactivation of retinoic acid signalling pathway target genes and cell differentiation induction in a dose- and time-dependent manner. Together, these results indicate that NLS-RARα blocks cell differentiation by inhibiting the retinoic acid signalling pathway.

大多数急性早幼粒细胞白血病（APL）病例的特征是PML-RARα融合基因。先前的研究表明，中性粒细胞弹性蛋白酶（NE）可以裂解PML-RARα，对于APL的发展很重要。在这里，我们证明了PML-RARα的裂解产物之一NLS-RARα可以通过抑制视黄酸信号通路内靶基因的表达来阻止细胞分化。逆转录聚合酶链反应（RT-PCR）和蛋白质印迹分析结果表明，NLS-RARα抑制了细胞分化标记蛋白CD11b和CEBPβ的表达，以及维甲酸信号通路目标基因RARβ和CEBPε的表达。研究表明，NLS-RARα与类维生素A X受体α（RXRα）形成异二聚体并与SMRT相互作用。当用全反式维甲酸（ATRA）处理时，与RARα相比，NLS-RARα的转录活性降低。此外，在高剂量的ATRA的存在下，NLS-RARα可以降解，并且随之而来的视黄酸信号通路靶基因的反式激活和细胞分化的诱导也呈剂量和时间依赖性。总之，这些结果表明，NLS-RARα通过抑制视黄酸信号通路来阻断细胞分化。