Widespread remodeling of the RNA editome underlies transcriptional and clinical heterogeneity in pediatric acute lymphoblastic leukemia

Abstract Aberrant RNA editing by adenosine deaminases is increasingly recognized as a source of transcriptional diversity in adult cancer, yet its role in pediatric leukemia remains poorly understood. Here, we systematically profiled RNA editing events from bulk RNA-seq data of 1,025 pediatric T-cell acute lymphoblastic leukemia (T-ALL) samples, 37 matched B-ALL diagnosis/relapse pairs, and 6 age-matched non-leukemic controls. We uncovered a widespread global increase in A-to-I editing in T-ALL, affecting both non-coding Alu elements and coding sequences. By contrast, B-ALL shows relatively modest increases in RNA editing at both diagnosis and relapse with no differences in ADAR1 levels. ADAR1 expression is strongly associated with double-stranded RNA (dsRNA) sensors and interferon signaling in T-ALL. Genelevel analyses highlight recurrent editing of oncogenic drivers and regulators of immune signaling, chromatin remodeling, and RNA processing. Unexpectedly, increased editing levels in select genes (CD247, PRKCA and TRAF3IP2.ASI in T-ALL; SPPL3 in B-ALL) were significantly associated with better patient survival, suggesting a potential prognostic role for editing dysregulation at individual gene levels. Together, these results deepen our understanding of the pediatric ALL transcriptome landscape and provided novel candidate regulators and therapeutic targets for future mechanistic and translational investigation. Competing Interest Statement The authors have declared no competing interest. Data availability The normal pediatric PBMC and B-ALL RNA-seq datasets were obtained from NCI TARGET. The results published here are in whole or part based upon data generated by the Therapeutically Applicable Research to Generate Effective Treatments (https://www.cancer.gov/ccg/research/genome-sequencing/target) initiative, phs000464 and phs000471. The data used for this analysis are available at the Genomic Data Commons (https://portal.gdc.cancer.gov). The T-ALL RNA-seq dataset was obtained and analyzed based in whole or in part upon data generated by Gabriella Miller Kids First Pediatric Research Program projects phs002276, and were accessed from the Kids First Data Resource Portal ( https://kidsfirstdrc.org/ and/or dbGaP (www.ncbi.nlm.nih.gov/gap). The T-ALL with ADAR1 knockdown was obtained from GEO:GSE221112.