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Giacopelli, B.* ; Wang, M.* ; Cleary, A.* ; Wu, Y.Z.* ; Schultz, A.R.* ; Schmutz, M.* ; Blachly, J.S.* ; Eisfeld, A.K.* ; Mundy-Bosse, B.* ; Vosberg, S. ; Greif, P.A.* ; Claus, R.* ; Bullinger, L.* ; Garzon, R.* ; Coombes, K.R.* ; Bloomfield, C.D.* ; Druker, B.J.* ; Tyner, J.W.* ; Byrd, J.C.* ; Oakes, C.C.*

DNA methylation epitypes highlight underlying developmental and disease pathways in acute myeloid leukemia.

Genome Res. 31, 747-761 (2021)
Verlagsversion DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Gene-expression Profiles; Stem-cells; Regulatory Elements; Epigenomic Analysis; Aml; Mutations; Cancer; Phenotype; Hypermethylation; Differentiation
ISSN (print) / ISBN 1088-9051
e-ISSN 1549-5469
Zeitschrift Genome Research
Quellenangaben Band: 31, Heft: 5, Seiten: 747-761 Artikelnummer: , Supplement: ,
Verlag Cold Spring Harbor Laboratory Press
Verlagsort 1 Bungtown Rd, Cold Spring Harbor, Ny 11724 Usa
Begutachtungsstatus Peer reviewed
Förderungen BeatAMLConsortium
National Cancer Institute (NCI)
Howard Hughes Medical Institute
National Institutes of Health/NCI
Mark Foundation for Cancer Research
Silver Family Foundation
National Cancer Institute
Deutsche Jose Carreras Leukamie-Stiftung
German Cancer Aid
Gabrielle's Angel Foundation for Cancer Research
Ohio State University Comprehensive Cancer Center (OSUCCC)