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Demethylator phenotypes in acute myeloid leukemia
Andrew D Kelly1, Jozef Madzo1, Priyanka Madireddi1
1Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
Leukemia
|March 21, 2018
Summary
Researchers identified two distinct DNA demethylator phenotypes (DMPs) in acute myeloid leukemia (AML). These DMPs, DMP.1 and DMP.2, show distinct genetic mutations and gene expression patterns, impacting AML prognosis.
Area of Science:
- Epigenetics
- Cancer Genomics
- Hematologic Malignancies
Background:
- Acute myeloid leukemia (AML) is characterized by epigenetic dysregulation, including DNA hypermethylation and CpG island methylator phenotypes (CIMPs).
- Global hypomethylation is recognized in cancer, but distinct DNA demethylator phenotypes (DMPs) in AML remain uncharacterized.
Purpose of the Study:
- To investigate the existence and characteristics of distinct DNA demethylator phenotypes (DMPs) in acute myeloid leukemia (AML).
- To explore the genetic mutations, gene expression profiles, and prognostic implications associated with identified DMPs in AML.
Main Methods:
- Utilized Illumina 450k arrays on 194 The Cancer Genome Atlas (TCGA) AML patient samples.
- Applied hierarchical clustering to identify distinct DMPs.
- Integrated independent 450k datasets (236 additional cases) for validation and analyzed RNA-sequencing data.
Main Results:
- Identified two distinct DMPs: DMP.1 (associated with NPM1, FLT3, DNMT3A mutations) and DMP.2 (associated with t(8;21), inv(16), t(15;17) rearrangements).
- Observed distinct gene expression patterns: immune response genes upregulated in DMP.1 and developmental genes in DMP.2.
- Demonstrated prognostic significance of DMP status, independent of age and cytogenetics, in both initial and validation cohorts.
Conclusions:
- The study establishes the existence of distinct DNA demethylator phenotypes (DMPs) in AML, linked to specific genetic alterations and clinical outcomes.
- These findings suggest that DMPs play a role in AML pathogenesis and offer potential for refining risk stratification strategies.
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