Cuproptosis-related lncRNAs as potential biomarkers of AML prognosis and the role of lncRNA HAGLR/miR-326/CDKN2A regulatory axis in AML.

Acute myeloblastic leukemia (AML) is the most prevalent form of AML in adults. Despite the availability of various treatment options, including radiotherapy and chemotherapy, many patients fail to respond to treatment or relapse. Copper is a necessary cofactor for all organisms; however, it turns toxic when concentrations reach a certain threshold maintained by homeostatic systems that have been conserved through evolution. However, the mechanism through which excess copper triggers cell death remains unknown. In this study, data on long non-coding RNAs (lncRNAs) related to cuproptosis were retrieved from publicly available databases. LASSO and univariate and multivariate Cox regression analyses were performed to establish an lncRNA model associated with cuproptosis specific to AML. To investigate the risk model, the Kaplan-Meier curve, principal component analysis, functional enrichment analysis, and nomographs were employed. The underlying clinicopathological characteristics were determined, and drug sensitivity predictions against the model were identified. Six cuproptosis-related lncRNA-based risk models were identified as the independent prognostic factors. By regrouping patients using a model-based method, we were able to more accurately differentiate patients according to their responses to immunotherapy. In addition, prospective compounds targeting AML subtypes have been identified. Using qRT-PCR, we examined the expression levels of six cuproptosis-associated lncRNAs in 30 clinical specimens. The cuproptosis-associated lncRNA risk-scoring model developed herein has implications in monitoring AML prognosis and in the clinical prediction of the response to immunotherapy. Furthermore, we identified and verified the ceRNA of the cuproptosis-related lncRNA HAGLR/miR-326/CDKN2A regulatory axis using bioinformatic tools. HAGLR is highly expressed in AML and AML cell lines. HAGLR inhibition significantly reduced the proliferation of AML cells and promoted apoptosis. Elesclomol promotes the degradation of CDKN2A and inhibits the proliferation of AML cells. Elesclomol combined with si-HAGLR inhibited the AML progression of AML both in vitro and in vivo.