ncRNAs Linked to CLL Outcomes, Meta-Analysis Finds

A comprehensive systematic review and meta-analysis of 39 studies involving 4905 patients with chronic lymphocytic leukemia (CLL) shows that dysregulation of non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), is consistently associated with poor clinical outcomes. Published in BMC Cancer, the findings indicate that expression abnormalities in these regulatory RNAs are associated with shorter overall survival (OS), reduced progression-free survival (PFS), and earlier time to treatment (TTT).¹

CLL is characterized by substantial biological heterogeneity, and current predictors, including IGHV mutational status, cytogenetic abnormalities, and selected genetic mutations, do not fully explain differences in disease trajectories.² Traditional prognostic tools such as Rai and Binet staging, FISH-based cytogenetic profiling, and IGHV mutational status remain central to risk assessment, but emerging ncRNA biomarkers appear to provide added prognostic insight.

An important advantage of ncRNAs as potential biomarkers is their stability in circulating body fluids, which may facilitate not only diagnostic but also longitudinal, non-invasive prognostic monitoring.³ The authors explained, “changes in ncRNA levels may occur before detectable changes in conventional methods, allowing for early diagnosis and faster intervention,” positioning ncRNAs “as promising candidates for diagnostic and prognostic biomarkers in CLL, potentially improving patient management and enabling personalized treatment strategies.”¹

Across 26 studies evaluating 45 miRNAs in 2997 patients, miRNA dysregulation correlated with significantly shorter OS (HR, 2.41; 95% CI, 2.03-2.86), shorter PFS (HR, 1.82; 95% CI, 1.29-2.57), and earlier TTT (HR, 2.39; 95% CI, 2.04-2.79). Subgroup analyses indicated that smaller cohorts tended to overestimate PFS effects, while high-bias studies inflated OS and TTT estimates. Among the evaluated markers, miR-29c, miR-34a, miR-181b, and miR-223 demonstrated the strongest and most consistent prognostic associations, reflecting patterns reported across individual analyses of these miRNAs in CLL and other malignancies.

Beyond miRNAs, six studies assessing 14 distinct lncRNAs in 1026 patients identified significant associations between lncRNA dysregulation and adverse outcomes. Altered lncRNA expression was associated with poorer OS (HR, 2.76; 95% CI, 2.36-3.22) and earlier TTT (HR, 2.53; 95% CI, 2.06-3.10). Lnc-IRF2-3 and multiple ferroptosis-related lncRNAs, including SBF2-AS1 and LINC00494, demonstrated the highest prognostic value for OS. LncRNA-p21 showed the strongest relationship with PFS, though the number of available studies was limited.

The circRNA findings showed the largest effect sizes among the ncRNA classes. Seven studies evaluating 10 circRNAs in 882 patients showed that circRNA dysregulation was associated with substantially shorter survival (HR, 3.91; 95% CI, 3.49-4.39). CircLNPEP and CircCAT6A emerged as the most prognostically relevant markers, and subgroup analyses suggested stronger effects in larger cohorts and low-bias studies. The authors emphasize that circRNAs, because of their covalently closed circular structures and high molecular stability, may make them particularly promising candidates for biomarker development, although functional characterization remains incomplete.

Nevertheless, the review noted several methodologic limitations that may hinder broad immediate clinical adoption, including bias from indirect HR extraction, lack of standardized outcome or prognostic factor definitions, and variable reporting for lost-to-follow-up rates and measurement platforms. The authors found that study attrition (81.5%), prognostic factor measurement (52%), and outcome measurement (39%) were the most frequent sources of bias, with only 1 study achieving a low risk of bias across all domains. Approximately 44% of reported hazard ratios were assessed indirectly using Kaplan-Meier curves, which the authors acknowledge as a potential limitation given the risk of extraction inaccuracy.

Despite these limitations, the collective evidence supports a consistent association between dysregulated ncRNA expression and clinically meaningful differences in survival and disease progression. The authors suggest that the ncRNAs highlighted in this study “should not only be considered as prognostic biomarkers, but also as functionally actionable regulators with therapeutic promise.” They note, however, that translating these findings into clinical practice will require functional studies to clarify biological mechanisms, improved delivery technologies for ncRNA-directed therapies, and incorporation of ncRNA frameworks into future clinical trial designs. They conclude that such advances could ultimately support the development of ncRNA-based precision treatments for patients with CLL.

References

1. Aghayan AH, Arab A, Haddadi S, et al. Investigating the prognostic value of non-coding RNAs in chronic lymphocytic leukemia: insights from a systematic review and meta-analysis. BMC Cancer. 2025;25(1):1739. doi:10.1186/s12885-025-15117-5
2. Braish J, Cerchione C, Ferrajoli A. An overview of prognostic markers in patients with CLL. Front Oncol. 2024;14:1371057. doi:10.3389/fonc.2024.1371057
3. Katayama ES, Hue JJ, Loftus AW, et al. Stability of microRNAs in serum and plasma reveal promise as a circulating biomarker. Noncoding RNA Res. 2025;15:132-141. doi:10.1016/j.ncrna.2025.08.001