Influence of comorbidity burden and senescence on patterns of DNA methylation in patients with Chronic Lymphocytic Leukemia
Year: 2026
Type: article
Study design: Observational Study
Abstract: Chronic lymphocytic leukemia (CLL) is characterized by a heterogeneous clinical course, with some patients showing slowly progressive disease and others progressing rapidly, requiring early intervention. This variability complicates treatment decision-making and highlights the need for reliable prognostic indicators. One emerging factor is frailty, a multidimensional syndrome reflecting cumulative physiological decline across organ systems. In oncology, frailty is often estimated using the Cumulative Illness Rating Scale (CIRS), a weighted comorbidity index with prognostic value. However, the biological basis of CIRS and its relationship to molecular aging remain poorly understood. Because frailty shares physiological features with aging, biological aging markers, particularly epigenetic age derived from DNA methylation (DNAm) patterns, may offer mechanistic insight. Epigenetic age acceleration, where biological age exceeds chronological age, has been proposed as a predictor of frailty and disease risk. However, the accuracy of epigenetic clocks varies by tissue type, population, and training data. Cellular senescence, a hallmark of aging associated with a pro-inflammatory secretory phenotype, may also reshape the epigenetic landscape and influence these clocks. Yet whether senescence contributes to epigenetic age acceleration and clinical frailty in CLL remains unclear. To investigate this, we profiled DNAm in both malignant B cells and non-malignant immune cells from CLL patients aged 52–98 years, examining associations between epigenetic aging, CIRS scores, and known prognostic markers, including IGHV mutation status and CD38 expression. We also analyzed T cell subsets to determine whether cellular senescence affected epigenetic age estimates or their predictive accuracy. Our findings show that epigenetic age acceleration does not correlate with CIRS scores or poor prognostic markers in CLL. Epigenome-wide association studies (EWAS) identified no significant CpG sites associated with high CIRS scores. In addition, cellular senescence markers did not influence epigenetic clock accuracy or affect estimates of cell composition. These results suggest that DNAm-based epigenetic clocks, while valuable for studying aging, may have limited utility in capturing clinical frailty, at least as defined by CIRS, in CLL. Overall, this study highlights the complexity of aging and frailty in hematological malignancies and underscores the importance of integrating molecular, clinical, and immunological data when developing biomarkers for risk stratification and planning.
Source: Mspace (University of Manitoba)
Author: Fauni, Maria Shenna
Institution: University of Manitoba
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7153688406