Abstract
Recent studies have evidenced that ubiquitin-specific proteases (USPs) are associated with the occurrence and drug resistance of T-cell acute lymphoblastic leukemia (T-ALL). N6-methyladenosine (m6A) demethylase AlkB homolog 5 (ALKBH5) exerts a carcinogenic effect in human cancers and improves the mRNA stability of USPs. Whether ubiquitin specific protease 1 (USP1) controls chemoresistance in T-ALL is unknown. Our study demonstrated that USP1, Aurora kinase B (Aurora B) and ALKBH5 levels were highly expressed in glucocorticoid (GC)-resistant T-ALL patients and cells (CEM-C1). High expression of USP1 was correlated to the poor prognosis of T-ALL patients. Silencing USP1 increased CEM-C1 cell sensitivity to dexamethasone (Dex), reduced cell invasion, promoted cell apoptosis, and ameliorated glucocorticoid receptor (GR) expression. USP1 mediated T-ALL chemoresistance by interacting with Aurora B. Overexpression of USP1 reversed the promotive effects of Aurora B inhibitor on the sensitivity of CEM-C1 cells to Dex, cell apoptosis and GR level and the inhibition effect on cell invasion. Downregulation of ALKBH5 reduced the levels of USP1 and Aurora B, facilitated CEM-C1 cell sensitivity to Dex, apoptosis and GR expression, suppressed cell invasion. However, overexpression of USP1 reversed all the effects of ALKBH5 on CEM-C1 cells. In vivo results showed that tail vein injection of sh-USP1 resulted in a significant prolongation of mouse survival and maintained the normal weight of mice compared to the Dex group, reduced USP1 expression and facilitated GR expression. In conclusion, downregulation of USP1 ameliorated glucocorticoid resistance of T-cell acute lymphoblastic leukemia cells through suppressing Aurora B expression and elevating GR level.
Modulation of Glucocorticoid Resistance in Pediatric T-cell Acute Lymphoblastic Leukemia by Increasing BIM Expression with the PI3K/mTOR Inhibitor BEZ235
