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Updated: May 5, 2026
Comprehensive DNA Methylation Analysis Using a Methyl-CpG-binding Domain Capture-based Method in Chronic Lymphocytic Leukemia Patients
Published on: June 16, 2017
Clinical response to azacitidine in MDS is associated with distinct DNA methylation changes in HSPCs
Julie A I Thoms1, Feng Yan2, Henry R Hampton3
1School of Biomedical Sciences, University of New South Wales, Sydney, NSW, Australia. j.thoms@unsw.edu.au.
Abstract:
Hypomethylating agents are frontline therapies for myelodysplastic neoplasms (MDS), yet clinical responses remain unpredictable. We conducted a phase 2 trial comparing injectable and oral azacitidine (AZA) administered over one or three weeks per four-week cycle, with the primary objective of investigating whether response is linked to in vivo drug incorporation or DNA hypomethylation. Our findings show that injection results in higher drug incorporation, but lower DNA demethylation per cycle, while global DNA methylation levels in mononuclear cells are comparable between responders and non-responders. However, hematopoietic stem and progenitor cells (HSPCs) from responders exhibit distinct baseline and early treatment-induced CpG methylation changes at regulatory regions linked to tissue patterning, cell migration, and myeloid differentiation. By cycle six-when clinical responses typically emerge-further differential hypomethylation in responder HSPCs suggests marrow adaptation as a driver of improved hematopoiesis. These findings indicate that intrinsic baseline and early drug-induced epigenetic differences in HSPCs may underlie the variable clinical response to AZA in MDS.
Insights
Clinical response to azacitidine (AZA) in myelodysplastic neoplasms (MDS) is unpredictable. This study found that patient responders have unique baseline and early epigenetic differences in hematopoietic stem cells, influencing treatment outcomes.
Area of Science:
- Oncology
- Epigenetics
- Hematology
Background:
- Hypomethylating agents like azacitidine (AZA) are standard treatments for myelodysplastic neoplasms (MDS).
- Predicting patient response to AZA remains a clinical challenge.
Purpose of the Study:
- To investigate the relationship between azacitidine (AZA) administration routes, drug incorporation, DNA hypomethylation, and clinical response in MDS.
- To identify early epigenetic markers in hematopoietic stem and progenitor cells (HSPCs) that predict treatment response.
Main Methods:
- A phase 2 clinical trial comparing injectable and oral AZA administration.
- Analysis of in vivo drug incorporation, DNA methylation levels in mononuclear cells and HSPCs.
- Assessment of CpG methylation changes in regulatory regions of HSPCs at baseline and during treatment.
Main Results:
- Injectable AZA led to higher drug incorporation but lower DNA demethylation per cycle compared to oral AZA.
- Global DNA methylation in mononuclear cells did not differ between responders and non-responders.
- Responders showed distinct baseline and early treatment-induced CpG methylation changes in HSPCs, particularly in regions related to myeloid differentiation and tissue patterning.
Conclusions:
- Intrinsic baseline epigenetic differences in HSPCs may predict AZA response in MDS.
- Early drug-induced epigenetic modifications in HSPCs, rather than global methylation changes, are associated with clinical response.
- Marrow adaptation driven by epigenetic changes in HSPCs could be a key factor in improved hematopoiesis and treatment outcomes.
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