Journal
GENOME RESEARCH
Volume 31, Issue 5, Pages 747-761Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gr.269233.120
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Funding
- Ohio State University Comprehensive Cancer Center (OSUCCC)
- National Cancer Institute (NCI) [P30 CA016058]
- Howard Hughes Medical Institute
- National Institutes of Health/NCI [U54 CA224019, U01 CA217862]
- Mark Foundation for Cancer Research
- Silver Family Foundation
- National Cancer Institute [1R01CA183947, 1U01CA217862, 1U54CA224019]
- Deutsche Jose Carreras Leukamie-Stiftung
- German Cancer Aid [DKH 110530]
- Gabrielle's Angel Foundation for Cancer Research
- BeatAMLConsortium
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The study analyzed genome-wide DNA methylation in 649 AML patients and identified 13 epitypes, revealing associations between different epitypes and recurrent mutations in patients. Results showed unique DNA methylation patterns among epitypes, with stem-cell-like epitypes associated with poor survival and up-regulated stem cell gene expression signatures. Additionally, a DNA methylation signature involving STAT motifs associated with FLT3-ITD mutations was identified, and DNA methylation signatures were stable at relapse for most patients, with rare epitype switching observed.
Acute myeloid leukemia (AML) is a molecularly complex disease characterized by heterogeneous tumor genetic profiles and involving numerous pathogenic mechanisms and pathways. Integration of molecular data types across multiple patient cohorts may advance current genetic approaches for improved subclassification and understanding of the biology of the disease. Here, we analyzed genome-wide DNA methylation in 649 AML patients using Illumina arrays and identified a configuration of 13 subtypes (termed epitypes) using unbiased clustering. Integration of genetic data revealed that most epitypes were associated with a certain recurrent mutation (or combination) in a majority of patients, yet other epitypes were largely independent. Epitypes showed developmental blockage at discrete stages of myeloid differentiation, revealing epitypes that retain arrested hematopoietic stem-cell-like phenotypes. Detailed analyses of DNA methylation patterns identified unique patterns of aberrant hyper- and hypomethylation among epitypes, with variable involvement of transcription factors influencing promoter, enhancer, and repressed regions. Patients in epitypes with stem-cell-like methylation features showed inferior overall survival along with up-regulated stem cell gene expression signatures. We further identified a DNA methylation signature involving STAT motifs associated with FLT3-ITD mutations. Finally, DNA methylation signatures were stable at relapse for the large majority of patients, and rare epitype switching accompanied loss of the dominant epitype mutations and reversion to stem-cell-like methylation patterns. These results show that DNA methylation-based classification integrates important molecular features of AML to reveal the diverse pathogenic and biological aspects of the disease.
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