Hsa_circ_0015278 Regulates FLT3-ITD AML Progression via Ferroptosis-Related Genes

SIMPLE SUMMARY: Acute myeloid leukemia (AML), especially the FLT3-ITD mutation subtype, has a poorer prognosis and higher risk of recurrence, which seriously threatens human health. Ferroptosis, an iron-dependent regulated cell death, is involved in the development and progression of AML. The mechanism by which circRNAs regulate the pathogenesis and prognosis of FLT3-ITD mutant-type AML through ferroptosis-related genes (FerRGs) remains unclear. In the present study, we aimed to decipher the pathogenic role of circRNAs in AML with FLT3-ITD mutation. Encouragingly, we discovered a circRNA, hsa_circ_0015278, that regulates ferroptosis-related genes by sponging miRNAs to promote FLT3-ITD AML progression. Furthermore, ferroptosis-related genes with prognostic value contribute to FLT3-ITD AML progression by regulating the tumor microenvironment. In conclusion, we constructed a ceRNA regulatory network involving hsa_circ_0015278/miRNAs/FerRGs, and the hsa_circ_0015278 signaling axis contributes to the identification of potential diagnostic and prognostic biomarkers and provides new insight into the pathogenesis and therapeutic targets of AML with FLT3-ITD mutation. ABSTRACT: AML with the FLT3-ITD mutation seriously threatens human health. The mechanism by which circRNAs regulate the pathogenesis of FLT3-ITD mutant-type AML through ferroptosis-related genes (FerRGs) remains unclear. Differentially expressed circRNAs and mRNAs were identified from multiple integrated data sources. The target miRNAs and mRNAs of the circRNAs were predicted using various databases. The PPI network, ceRNA regulatory network, GO, and KEGG enrichment analyses were performed. The “survival” and the “pROC” R packages were used for K-M and ROC analysis, respectively. GSEA, immune infiltration analysis, and clinical subgroup analysis were performed. Finally, circRNAs were validated by Sanger sequencing and qRT-PCR. In our study, 77 DECircs-1 and 690 DECircs-2 were identified. Subsequently, 11 co-up-regulated DECircs were obtained by intersecting DECircs-1 and DECircs-2. The target miRNAs of the circRNAs were screened by CircInteractome, circbank, and circAtlas. Utilizing TargetScan, ENCORI, and miRWalk, the target mRNAs of the miRNAs were uncovered. Ultimately, 73 FerRGs were obtained, and the ceRNA regulatory network was constructed. Furthermore, MAPK3 and CD44 were significantly associated with prognosis. qRT-PCR results confirmed that has_circ_0015278 was significantly overexpressed in FLT3-ITD mutant-type AML. In summary, we constructed the hsa_circ_0015278/miRNAs/FerRGs signaling axis, which provides new insight into the pathogenesis and therapeutic targets of AML with FLT3-ITD mutation.