MicroRNAs as potential prognostic biomarkers in acute lymphoblastic leukemia: a systematic review, meta-analysis, and...

Acute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized by malignant transformation of lymphoid precursor cells. ALL prognosis differs considerably, especially between pediatric patients and adult patients, with poor response to therapy in adults. MicroRNAs (miRNAs), small non-coding RNAs that regulate the expression of genes, are possible cancer biomarkers that predict cancer prognosis. This systematic review and meta-analysis evaluates miRNAs as prognostic biomarkers in ALL and extends the findings through ceRNA network and single-cell RNA seq analyses of validated target genes.

We systematically searched PubMed, SCOPUS, and Web of Science (WOS) to identify studies that compared miRNA expression with the survival of ALL patients following the PRISMA guidelines. We reviewed these studies for their methodological quality, and hazard ratios (HRs) were extracted to examine miRNA expression and survival endpoints of overall survival (OS), disease-free survival (DFS), and relapse-free survival (RFS). We also applied single-cell RNA sequencing (scRNA-seq) and a competing endogenous RNA (ceRNA) network to study miRNA targets.

miR-335 showed a significant protective role with a pooled HR of 0.29 (95% CI, 0.12-0.68), miR-210 with a pooled HR of 0.22 (95% CI, 0.06-0.84), and miR-125b with a pooled HR of 0.39 (95% CI, 0.16-0.95) based on 22 examined studies involving 1974 patients. These miRNAs were correlated with improved OS, DFS, and RFS. We identified potential targets, whose functions were examined within key biological pathways through a ceRNA network. In various immune cell types, comparisons of B-ALL and T-ALL with normal cells showed that 36 and 98 target genes, respectively, were upregulated, while 21 and 19 genes were downregulated. Additionally, when comparing T-ALL to B-ALL cells, 70 target genes had increased expression, and 13 genes had decreased expression. Among all analyzed lineages, leukemic blast cells exhibited the most consistent and pronounced alterations in the expression of validated miRNA target genes, suggesting that blasts are the primary population influenced by these regulatory interactions in ALL.

These findings support miRNAs as valuable prognostic biomarkers for ALL with potential for personalized therapy. The context-dependent role of these miRNAs highlights the need for confirmation through large, multicenter trials. The constructed ceRNA network provides useful insights into their regulatory mechanisms, opening new directions for therapeutic strategies.