TY  - JOUR
A1  - Giacopelli, Brian
A1  - Wang, Min
A1  - Cleary, Ada
A1  - Wu, Yue-Zhong
A1  - Schultz, Anna Reister
A1  - Schmutz, Maximilian
A1  - Blachly, James S.
A1  - Eisfeld, Ann-Kathrin
A1  - Mundy-Bosse, Bethany
A1  - Vosberg, Sebastian
A1  - Greif, Philipp A.
A1  - Claus, Rainer
A1  - Bullinger, Lars
A1  - Garzon, Ramiro
A1  - Coombes, Kevin R.
A1  - Bloomfield, Clara D.
A1  - Druker, Brian J.
A1  - Tyner, Jeffrey W.
A1  - Byrd, John C.
A1  - Oakes, Christopher C.
T1  - DNA methylation epitypes highlight underlying developmental and disease pathways in acute myeloid leukemia
Y1  - 2021/05/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 747 
EP  - 761 
DO  - 10.1101/gr.269233.120 
VL  - 31 
IS  - 5 
UR  - http://genome.cshlp.org/content/31/5/747.abstract 
N2  - 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. 
ER  -