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Comprehensive DNA Methylation Analysis Using a Methyl-CpG-binding Domain Capture-based Method in Chronic Lymphocytic Leukemia Patients
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Continuous DNA Methylation Deconvolution-Based Surrogate for B-Cell Differentiation State in CLL.

Jeffrey Hage1,2, Lauren Wainman3, Fiyinfoluwa Kolawole1,2

  • 1Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Lebanon, NH, USA.

Biorxiv : the Preprint Server for Biology
|September 26, 2025
PubMed
Summary
This summary is machine-generated.

Chronic Lymphocytic Leukemia (CLL) subtypes are epigenetically classified using a new B-Index metric. This B-Index reveals distinct cell origins for mutated and unmutated CLL, offering insights into disease mechanisms.

Keywords:
B-memory-likeB-naive-likeCLLCell-of-OriginChronic Lymphocytic LeukemiaDNA MethylationDeconvolutionEpigeneticsTranscription FactorTumor Burden

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Area of Science:

  • Hematology
  • Epigenetics
  • Cancer Biology

Background:

  • Chronic Lymphocytic Leukemia (CLL) has two main subtypes: mutated (M-CLL) and unmutated (U-CLL).
  • These subtypes are believed to originate from different B-cell differentiation stages.
  • Understanding the cell of origin is crucial for deciphering CLL pathogenesis.

Purpose of the Study:

  • To develop a continuous epigenetic metric for CLL differentiation.
  • To investigate the cell of origin for M-CLL and U-CLL subtypes.
  • To explore epigenetic signals related to tumor burden and potential viral associations.

Main Methods:

  • Genome-scale DNA methylation profiling of 89 CLL samples.
  • Application of reference-based cell deconvolution techniques.
  • Development of a B-cell epigenetic similarity scale (B-Index).

Main Results:

  • The B-Index accurately classifies CLL subtypes (98.8%) with a stronger epigenetic signal than IGHV percent identity.
  • U-CLL exhibits an epigenetic profile more similar to memory B cells than naive B cells.
  • An epigenetic signal associated with tumor burden and potential Epstein-Barr Virus infection was identified.

Conclusions:

  • The B-Index provides epigenetic evidence for distinct CLL initiation mechanisms and cell of origin.
  • U-CLL appears to originate from a more differentiated B-cell lineage.
  • The developed deconvolution approach is applicable to other cancers with diverse subtypes.