Disease Stage- and Risk-Associated RNA Editing Signatures in Acute Myeloid Leukemia and Their Utility for Peripheral Blood-Based Assessment

Abstract

RNA editing is a widespread post-transcriptional regulatory mechanism, but its role in acute myeloid leukemia (AML) remains incompletely understood. We analyzed RNA editing in 59 paired diagnosis-relapse AML samples and eight age-matched healthy controls using a stringent discovery pipeline and beta-binomial regression framework accounting for overdispersion and repeated measurements. A total of 166,323 high-confidence RNA editing sites mapping to 5,917 genes were identified. Of tested sites, 1.2%-3.6% varied significantly by disease stage or ELN-2022 risk group. Disease stage-specific editing signatures distinguished healthy controls, diagnosis, and relapse samples, with relapse-associated signals validated in an independent AML cohort. ELN-2022 risk-specific editing signatures showed substantial overlap between intermediate- and adverse-risk groups. Cross-cohort analyses identified four bone marrow (BM) editing sites in TMEM165, COQ4, TIMM17A, and PLXDC2 reproducibly associated with relapse and one peripheral blood (PB) editing site in ABHD18 elevated in higher-risk ELN-2022 groups. Most editing sites were shared between BM and PB; only 2.1%-2.3% exhibited tissue-specific differences. Higher global editing levels were correlated with leukemic state, white blood cell count, and selected clinical features. These findings identify reproducible RNA editing signatures linked to AML disease stage and risk and support the use of RNA editing biomarkers for PB disease assessment.