The hidden regulators: Non-coding RNAs in KMT2A-rearranged acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) driven by KMT2A rearrangements (KMT2A-r) is an aggressive hematologic malignancy with poor prognosis and a high incidence in infants. While KMT2A fusion proteins drive leukemogenesis through transcriptional dysregulation, recent discoveries have highlighted the pivotal role of non-coding RNAs (ncRNAs) in shaping the molecular and epigenetic landscape of this disease. These key regulators of gene expression influence chromatin dynamics, transcriptional activation, and post-transcriptional control. Circular RNAs (circRNAs) contribute to genome instability and facilitate chromosomal translocations, while some fusion-derived circRNAs (f-circRNAs) sustain oncogenic signaling and promote chemoresistance. Long non-coding RNAs (lncRNAs) orchestrate transcriptional programs that maintain leukemic stem cell properties and reinforce aberrant self-renewal pathways. MicroRNAs (miRNAs) modulate critical oncogenic networks by regulating KMT2A fusion transcripts and downstream effectors, thereby impacting drug resistance, apoptosis, and proliferation. Meanwhile, enhancer RNAs (eRNAs) fine-tune transcriptional activity and epigenetic regulation, influencing KMT2A target gene expression and chromatin accessibility. Collectively, these ncRNAs integrate into the complex regulatory circuits of KMT2A-r ALL, revealing their potential as biomarkers for disease classification, risk stratification, and treatment response prediction. Understanding their interplay with KMT2A fusion proteins not only provides new insights into leukemogenesis but also highlights promising opportunities for therapeutic intervention and precision medicine in this high-risk leukemia subtype.