MicroRNAs Emerge as Promising Biomarkers in DLBCL

MicroRNAs represent a powerful class of regulatory molecules in diffuse large B-cell lymphoma (DLBCL), offering insight into disease biology while holding promise as diagnostic, prognostic, and predictive biomarkers, highlight researchers of a new review. Outlining the potential of these molecules in Non-Coding RNA, the researchers note that as efforts converge on validated miRNA panels and harmonized analytical approaches, miRNA profiling may become an integral component of precision-guided care for patients with DLBCL.¹

Despite major advances in treatment, such as rituximab (Rituxan; Genentech and Biogen) and polatuzumab vedotin (Polivy; Genentech), approximately one-third of patients develop relapsed or refractory disease. The persistent unmet need has emphasized the need to identify biomarkers that can better predict prognosis, guide treatment decisions, and illuminate disease biology. Increasingly, miRNAs have emerged as key candidates in this space.

“Mounting evidence shows that miRNAs are key regulators of DLBCL initiation, progression, and treatment response,” described the researchers. “These small non-coding RNAs modulate apoptosis, proliferation, immune evasion, and drug resistance through post-transcriptional regulation of pivotal signaling pathways.”

It is now estimated that miRNAs regulate over 60% of human genes,² underscoring their broad biological impact. In cancer, dysregulated miRNA expression can promote tumor growth, immune evasion, and therapy resistance—or conversely suppress oncogenic signaling.

Within DLBCL, miRNA dysregulation is tightly integrated into the disease’s molecular architecture, detailed the review. Modern classification systems increasingly highlight genetic alterations that involve miRNA loci or miRNA-regulated pathways. Several oncogenic miRNAs, such as miR-155, miR-21, and the miR-17–92 cluster, play central roles in lymphoma pathogenesis by modulating pathways such as PI3K/AKT, NF-κB, and MYC signaling. At the same time, tumor-suppressive miRNAs such as miR-34a, miR-144, miR-181a, and miR-124-3p restrain proliferation and promote apoptosis, with their loss often linked to adverse outcomes.

Among the most extensively studied miRNAs is miR-155, a well-established oncomiR in B-cell malignancies. Overexpression of miR-155 promotes lymphoma cell survival and proliferation by suppressing tumor-suppressor genes such as SHIP1 and SOCS1, thereby enhancing PI3K/AKT signaling. Elevated miR-155 expression is particularly associated with the activated B-cell–like (ABC) subtype of DLBCL and with molecular clusters driven by chronic B-cell receptor and NF-κB signaling. While numerous studies support its diagnostic and prognostic potential, results remain inconsistent across cohorts, reflecting biological heterogeneity and methodological variability.

MiR-21 represents another canonical oncogenic miRNA with strong relevance in DLBCL. Frequently overexpressed in both tumor tissue and circulation, miR-21 promotes lymphoma progression by targeting tumor suppressors such as PTEN and FOXO1. Clinically, elevated miR-21 levels have been linked to poorer overall survival and shorter progression-free survival in patients receiving rituximab-based therapy. Its stability in blood samples makes miR-21 particularly attractive as a minimally invasive biomarker, although standardization of detection methods remains a challenge.

The miR-17–92 cluster, often referred to as “oncomiR-1,” further illustrates the oncogenic role of miRNAs in DLBCL, noted the researchers. Located on chromosome 13q31.3, this cluster is frequently amplified in germinal center B-cell–like (GCB) DLBCL. Overexpression of individual members of the cluster, such as miR-18a and miR-19a, has been associated with inferior survival outcomes, reinforcing the link between miRNA dysregulation and aggressive disease biology.

Conversely, several miRNAs function as tumor suppressors. MiR-34a, a direct transcriptional target of TP53, is frequently downregulated in DLBCL, particularly in cases with TP53 mutations or epigenetic silencing. Loss of miR-34a has been associated with chemotherapy resistance and poor prognosis, while its restoration enhances sensitivity to cytotoxic agents. Similarly, miR-181a suppresses NF-κB signaling and is associated with improved outcomes in ABC-like DLBCL, while miR-144 and miR-124-3p inhibit key oncogenic drivers such as BCL6 and MYC.

The group also detailed how, beyond tumor-intrinsic effects, miRNAs also shape the tumor microenvironment. MiRNAs such as miR-155 and miR-21 influence immune cell function, cytokine production, and immune checkpoint regulation, contributing to immune evasion and treatment resistance. Circulating miRNA signatures may therefore reflect not only tumor burden but also systemic immune dysregulation.

Despite their promise, the clinical translation of miRNA biomarkers faces important hurdles, wrote the researchers. Variability in study design, patient populations, sample types, and analytical platforms has led to inconsistent findings across studies. Standardized methodologies and prospective validation in well-defined cohorts will be essential before miRNAs can be reliably incorporated into clinical decision-making.

References

1. Panteli E, Koumpis E, Georgoulis V, et al. The role of microRNAs as potential biomarkers in diffuse large B-cell lymphoma. Non-Coding RNA. 2026;12(1):2. doi:10.3390/ncrna12010002

2. Xu P, Wu Q, Yu J, et al. A systematic way to infer the regulation relations of miRNAs on target genes and critical miRNAs in cancers. Front Genet. Published online March 30, 2020. doi:10.3389/fgene.2020.00278