NPM1-ALK binds NPM1 and FOXM1

Nuclear NPM-ALK binds to endogenous full-length NPM and FOXM1 in ALK+ ALCL cells as assessed by co-immunoprecipitation (Haque et al, 2019). Endogenous NPM1 likely bridges the interaction between NPM-ALK and FOXM1, as the FOXM1-binding region of NPM1 is not conserved in the fusion protein and NPM1-ALK has been shown to form heterodimers with NPM1 (Box et al, 2016; Khan et al, 2015; Bhat et al, 2011). Formation of this complex is required for FOXM1-dependent expression of target genes such as CCNB1 (Cyclin B1), and consistent with this, both NPM-ALK and FOXM1 are detected in complex with a biotinylated FOXM1-consensus containing DNA target in ALCL lines and bind to the CCNB1 promoter as assessed by ChIP (Haque et al, 2019).<br>STAT3 likely contributes to the NPM1-ALK:FOXM1 signaling axis, as lentiviral knockdown of FOXM1 decreases phosphorylation of both STAT3 and NPM1-ALK, as well as decreasing expression of CCNB1. The significance of FOXM1-dependent phosphorylation of STAT3 and NPM1-ALK remains to be clarified (Haque et al, 2019).

核NPM-ALK蛋白与ALK+ ALCL细胞内的内源性全长NPM和FOXM1蛋白通过共免疫沉淀技术相结合（Haque等人，2019年）。内源性NPM1蛋白很可能连接NPM-ALK与FOXM1之间的相互作用，因为NPM1蛋白的FOXM1结合区域在融合蛋白中并不保守，且NPM1-ALK已被证实可以与NPM1形成异源二聚体（Box等人，2016年；Khan等人，2015年；Bhat等人，2011年）。此复合体的形成对于依赖FOXM1表达靶基因如CCNB1（细胞周期蛋白B1）至关重要，与此一致的是，NPM-ALK和FOXM1在ALCL细胞系中与生物素化的FOXM1共识序列DNA靶标形成复合物，并通过ChIP技术检测到它们结合到CCNB1启动子（Haque等人，2019年）。STAT3蛋白可能对NPM1-ALK:FOXM1信号轴的调控发挥重要作用，因为敲低FOXM1的慢病毒转染会降低STAT3和NPM1-ALK的磷酸化，同时减少CCNB1的表达。FOXM1依赖性磷酸化STAT3和NPM1-ALK的重要性仍有待阐明（Haque等人，2019年）。