NLS-RARα blocks cell differentiation by inhibiting the retinoic acid signalling pathway

Abstract

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.