DNA methylation epitypes highlight underlying developmental and disease pathways in acute myeloid leukemia
- Brian Giacopelli1,
- Min Wang1,
- Ada Cleary1,
- Yue-Zhong Wu1,
- Anna Reister Schultz2,
- Maximilian Schmutz3,
- James S Blachly1,
- Ann-Kathrin Eisfeld1,
- Bethany Mundy-Bosse1,
- Sebastian Vosberg4,
- Philipp A. Greif4,
- Rainer Claus5,
- Lars Bullinger6,
- Ramiro Garzon1,
- Kevin R Coombes1,
- Clara D Bloomfield1,
- Brian J Druker2,
- Jeffrey W Tyner2,
- John C Byrd1 and
- Christopher C Oakes1,7
Abstract
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 sub-classification 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 demonstrated 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 upregulated 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 demonstrate that DNA methylation-based classification integrates important molecular features of AML to reveal the diverse pathogenic and biological aspects of the disease.
- Received July 23, 2020.
- Accepted March 9, 2021.
- Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International license), as described at http://creativecommons.org/licenses/by-nc/4.0/.
