NPM1c⁺-driven lncRNA dysregulation in AML: Mechanisms, Controversies and translational roadblocks

In the landscape of acute myeloid leukemia (AML) research, mutations in nucleophosmin 1 (NPM1) are the most prevalent genetic alterations. The leukemogenic mutant variant, NPM1c⁺, is associated with a distinct gene expression profile linked to leukemia, but the downstream oncogenic pathways remain only partially understood. Long non-coding RNAs (lncRNAs) are RNA molecules with known regulatory roles in human development and disease. Research implicates many lncRNAs in hematopoiesis and leukemogenesis, revealing correlations between their expression and clinical parameters in AML patients. While NPM1c⁺ AML exhibits a distinct lncRNA signature, it remains contentious whether these molecules are bona fide drivers or passenger events, and how their context-dependent functions can be therapeutically exploited. This review focuses on lncRNAs in NPM1c⁺ AML, highlighting their roles in pathogenesis, prognosis, and chemoresistance. By systematically elucidating the role of lncRNAs as pivotal factors in the diagnosis, treatment, and prognosis of NPM1c⁺ AML, this study addresses a gap in the existing literature. Our analysis of specific lncRNAs, such as HOTAIRM1, HOXB-AS3, CRNDE, HOXBLINC, LONA, IFEX9, XLOC_109948, and HOTTIP, enhances our understanding of the molecular mechanisms underlying AML in the context of NPM1c⁺. These findings lay the groundwork for developing targeted therapies and improved prognostic tools for NPM1c⁺AML.