Crizotinib-driven IL10RA gene expression in NPM1-ALK

Expression of IL10RA is upregulated in NPM1-ALK cells treated with crizotinib, contributing to an inhibition bypass mechanism. Upregulation of IL10RA stimulates STAT3 phosphorylation independent of NPM1-ALK and results in upregulation of STAT3-dependent targets such as MYC, IRF4 and CD30. In addition, phosphorylated STAT3 binds to the promoters of the IL10RA, IL10RB and IL10 genes in response to crizotinib treatment of NPM1-ALK cells, in this way setting up a positive feedback loop (Prokoph et al, 2020).

IL10RA在经克唑替尼处理的NPM1-ALK细胞中表达上调，此现象有助于抑制机制绕过。IL10RA的上调独立于NPM1-ALK，可刺激STAT3磷酸化，进而导致MYC、IRF4和CD30等STAT3依赖性靶点的上调。此外，磷酸化的STAT3在NPM1-ALK细胞接受克唑替尼治疗后，与IL10RA、IL10RB和IL10基因的启动子结合，从而形成正反馈回路（Prokoph et al., 2020）。