NONO promotes MYB expression and splicing by interacting with enhancer lncRNA MY34UE-AS in human leukemia cells.

Dysregulation of the transcription factor MYB plays a critical role in leukemia pathogenesis, progression, and prognosis; however, the detailed regulatory mechanisms of MYB remain unclear. Recently, we identified an enhancer long noncoding RNA (lncRNA) MY34UE-AS, which upregulates MYB expression. Here, we demonstrate that non-POU-domain-containing octamer binding protein (NONO) binds to MY34UE-AS through its RNA recognition motif 2 (RRM2) domain, thereby upregulating MYB expression and splicing. This interaction drives leukemia cell proliferation and migration. Our findings unveil a novel regulatory mechanism of MYB and propose the NONO-MY34UE-AS axis as a potential therapeutic target for leukemia. Impact statement Our study uncovers the NONO-MY34UE-AS-MYB regulatory axis in leukemia, revealing a new layer of MYB control. This mechanistic insight advances understanding of oncogenic transcription factor dysregulation and highlights potential therapeutic targets, offering new directions for leukemia research.