USP7 mutations are associated with adverse outcomes in pediatric T cell acute lymphoblastic leukemia and lymphoma.

Abstract

USP7 alterations in pediatric T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) remains incompletely understood. We investigated the clinical features and long-term outcomes associated with USP7 mutations in a cohort of 313 pediatric T-ALL/LBL patients. USP7 and NOTCH1 mutations were detected by Sanger sequencing and their association with prognosis were analyzed. Cox regression and nomogram models were used to evaluate prognostic importance. We identified 12 patients with USP7 heterozygous mutations (10 T-ALL, 2 T-LBL) with older age and higher proportion of not remission at day 15 morphological evaluation. Patients with USP7 mutation showed significantly worse event-free survival (EFS) and overall survival (OS) compared to wild-type cases, both in T-ALL and combined T-ALL/LBL cohorts. Concurrent analysis of USP7 and NOTCH1 mutations revealed USP7^mutNOTCH1^wt genotype was associated with the worst, whereas USP7^wtNOTCH1^mut was linked to the best EFS and OS in both T-ALL and T-ALL/LBL groups. USP7 mutation, pre-consolidation MRD ≥ 10^-4 and CNS leukemia were independent adverse factors for EFS, and the former two were also predictors for OS. USP7 mutation status was validated as the most influential prognostic factor, with prediction models including USP7 status showing enhanced accuracy. In conclusion, USP7 mutations define a subset of T-ALL/LBL patients with adverse outcomes on conventional intensive treatment.