DNA methylation epitypes highlight underlying developmental and disease pathways in acute myeloid leukemia
| Autor: | James S. Blachly, Anna Reister Schultz, Maximilian Schmutz, Christopher C. Oakes, Brian J. Druker, Bethany L. Mundy-Bosse, Min Wang, Sebastian Vosberg, Ramiro Garzon, Lars Bullinger, Philipp A. Greif, Ann-Kathrin Eisfeld, Rainer Claus, John C. Byrd, Clara D. Bloomfield, Yue Zhong Wu, Kevin R. Coombes, Brian Giacopelli, Ada C Cleary, Jeffrey W. Tyner |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Myeloid Biology 03 medical and health sciences 0302 clinical medicine Gene expression Genetics medicine Humans ddc:610 Promoter Regions Genetic Enhancer Transcription factor Genetics (clinical) 030304 developmental biology 0303 health sciences Research Myeloid leukemia Methylation DNA Methylation Phenotype Leukemia Myeloid Acute medicine.anatomical_structure Mutation DNA methylation 030217 neurology & neurosurgery |
| Zdroj: | Genome Res Genome Res. 31, 747-761 (2021) |
| ISSN: | 1549-5469 1088-9051 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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