Dysregulation of MicroRNA-181a-5p Targets TNFAIP3 to Promote MIF-CXCR4 Signaling and Immune Inflammatory Remodeling in Chronic Myeloid Leukemia.

[BACKGROUND] The non-coding RNAs, particularly microRNA-181a-5p target the expression of tumor necrosis factor alpha-induced protein 3 (TNFAIP3) a key negative regulator of NF-κB signaling and affect the levels of macrophage migration inhibitory factor (MIF) and chemokine receptor type 4 (CXCR4) in chronic myeloid leukamia (CML).

[METHODS] The study included 57 individuals with chronic myeloid leukemia (CML) and 33 healthy individuals. Hematological parameters (Hb, RBCs, WBCs and platelets) were assessed. The serum levels of MIF, TNFAIP3 and CXCR4 were measured using ELISA Technique. Quantitative real-time polymerase chain reaction was performed to assess miR-181a expression. The potential targets and immune associated pathways of miR-181a were predicted using bioinformatics tools including TargetScan, miRTarBase, STRING, DAVID, and Enrichr. Statistical analysis included ROC curve evaluation, Pearson correlation, and t-tests.

[RESULTS] Compared to controls, CML patients exhibited reduced platelets, Hb and RBC while elevated WBCs recorded. There were significantly elevated serum levels of MIF and CXCR4, and reduced levels of TNFAIP3 (p<0.01) in CML patients compared to control. Moreover, higher miR-181a expression (2.28 fold, p=0.0001) recorded in CML compared to control. Positive correlations were observed between miR-181a expression and both MIF and CXCR4 levels while TNFAIP3 exhibited a reverse correlation. ROC analysis showed that MIF (AUC = 0.873) and CXCR4 (AUC = 0.929) exhibited strong diagnostic performance while TNFAIP3 (AUC = 0.142) and miR-181a-5p (AUC = 0.201) demonstrated weak accuracy consistent with their opposite expression patterns between CML patients and healthy controls.

[CONCLUSION] The findings of this study suggested that increased miR-181a expression may be associated with reduced TNFAIP3 levels and modified NF-κB related inflammatory signaling in CML. These findings support the hypothesis in which miR-181a, MIF, and CXCR4 may contribute to immune dysregulation in CML as well as diagnostic biomarkers and promising therapeutic target.