Reflecting on 30 years of miRNA biology in malignant hematology: current challenges and future directions

MicroRNAs (miRNAs) are essential regulators of hematopoiesis, influencing stem cell maintenance, lineage specification, and differentiation. While their dysregulation has been widely implicated in hematological malignancies such as acute myeloid leukemia, progress toward clinical translation has been hindered by methodological inconsistencies, oversimplified interpretations, and model limitations. This viewpoint discusses the context-dependent nature of miRNA-mRNA interactions, the influence of isomiRs, and the impact of RNA-binding proteins and epitranscriptomic modifications on miRNA activity. We highlight the limitations of commonly used bulk sequencing and reductionist models, and advocate for more physiologically relevant systems, including hematopoietic organoids, single-cell and spatial transcriptomics, and CRISPR-based functional assays. Furthermore, we discuss advances in miRNA-targeted therapeutics, such as lipid nanoparticle delivery and anti-miRs. By integrating emerging technologies with standardized methodologies and biological complexity, miRNA research in hematology will uncover new regulatory mechanisms and therapeutic vulnerabilities, offering a robust path toward diagnostic, prognostic, and treatment applications.