Abstract
RNA modifications, collectively termed the epitranscriptome, constitute a dynamic layer of post-transcriptional regulation that governs RNA splicing, stability, localization, translation, and decay. In the hematopoietic system, these chemical marks influence stem cell fate, lineage specification, immune surveillance, and malignant transformation through context-dependent regulation of mRNA, tRNA, rRNA, and non-coding RNAs. Here, we focus on RNA modifications and editing events with emerging mechanistic and translational relevance in normal and malignant hematopoiesis, highlighting those implicated in stem cell dynamics, leukemic progression, and therapeutic resistance. Specifically, we discuss N⁶-methyladenosine (m⁶A), 5-methylcytosine (m⁵C), N⁷-methylguanosine (m⁷G), N⁴-acetylcytidine (ac⁴C), pseudouridine (Ψ), adenosine-to-inosine (A-to-I) editing, and RNA glycosylation. Particular attention is given to enzymes such as METTL3, METTL1, ADAR1, and NAT10, whose dysregulation sustains leukemic stem cell programmes, promotes immune evasion, and confers treatment resistance. With the first-in-class METTL3 inhibitor STC-15 now in early-phase clinical trials in solid tumours (NCT05584111, NCT06975293), and additional RNA-modifying enzyme inhibitors advancing preclinically, these pathways are emerging as therapeutically tractable, including in hematological cancers. Furthermore, integrating epitranscriptomic profiles into genomic risk frameworks may also improve disease stratification, minimal residual disease (MRD) monitoring, and the identification of targetable vulnerabilities. Together, these insights position RNA modifications as central to blood cancer biology and support their integration into next-generation diagnostic, prognostic, and therapeutic strategies.