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Comprehensive DNA Methylation Analysis Using a Methyl-CpG-binding Domain Capture-based Method in Chronic Lymphocytic Leukemia Patients
Published on: June 16, 2017
Loss of Dnmt3a induces CLL and PTCL with distinct methylomes and transcriptomes in mice
Staci L Haney1, Garland M Upchurch2, Jana Opavska2
1Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA.
Abstract:
Cytosine methylation of DNA is an epigenetic modification involved in the repression of genes that affect biological processes including hematopoiesis. It is catalyzed by DNA methyltransferases, one of which -DNMT3A- is frequently mutated in human hematologic malignancies. We have previously reported that Dnmt3a inactivation in hematopoietic stem cells results in chronic lymphocytic leukemia (CLL) and CD8-positive peripheral T cell lymphomas (PTCL) in EμSRα-tTA;Teto-Cre;Dnmt3afl/fl; Rosa26LOXPEGFP/EGFP (Dnmt3aΔ/Δ) mice. The extent to which molecular changes overlap between these diseases is not clear. Using high resolution global methylation and expression analysis we show that whereas patterns of methylation and transcription in normal B-1a cells and CD8-positive T cells are similar, methylomes and transcriptomes in malignant B-1a and CD8+ T cells are remarkably distinct, suggesting a cell-type specific function for Dnmt3a in cellular transformation. Promoter hypomethylation in tumors was 10 times more frequent than hypermethylation, three times more frequent in CLL than PTCL and correlated better with gene expression than hypermethylation. Cross-species molecular comparison of mouse and human CLL and PTCL reveals significant overlaps and identifies putative oncogenic drivers of disease. Thus, Dnmt3aΔ/Δ mice can serve as a new mouse model to study CLL and PTCL in relevant physiological settings.
Insights
DNA methyltransferase DNMT3A is crucial for preventing hematologic malignancies like chronic lymphocytic leukemia (CLL) and T cell lymphomas. Its inactivation leads to distinct molecular changes in B and T cells, highlighting cell-type specific roles in cancer development.
Area of Science:
- Epigenetics
- Molecular Biology
- Cancer Research
Background:
- Cytosine methylation of DNA is an epigenetic mechanism regulating gene expression.
- DNMT3A, a DNA methyltransferase, is frequently mutated in human hematologic malignancies.
- Dnmt3a inactivation in hematopoietic stem cells causes chronic lymphocytic leukemia (CLL) and CD8-positive peripheral T cell lymphomas (PTCL) in mice.
Purpose of the Study:
- To investigate the molecular overlap between Dnmt3a-driven CLL and PTCL.
- To determine the cell-type specific function of Dnmt3a in cellular transformation.
- To identify conserved molecular drivers of CLL and PTCL across species.
Main Methods:
- High-resolution global DNA methylation analysis.
- Gene expression profiling (transcriptome analysis).
- Cross-species molecular comparison of mouse and human cancers.
Main Results:
- Methylomes and transcriptomes of malignant B-1a and CD8+ T cells are distinct, unlike their normal counterparts.
- Promoter hypomethylation is more frequent than hypermethylation in tumors and more prevalent in CLL than PTCL.
- Hypomethylation strongly correlates with gene expression changes.
- Significant molecular overlaps between mouse and human CLL/PTCL were identified, revealing potential oncogenic drivers.
Conclusions:
- Dnmt3a plays a cell-type specific role in the development of hematologic malignancies.
- Dnmt3a-deficient mice provide a valuable model for studying CLL and PTCL in a physiological context.
- Understanding these molecular distinctions can inform targeted therapeutic strategies for distinct lymphoid cancers.
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