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

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Item Type:Article
Title:DNA methylation epitypes highlight underlying developmental and disease pathways in acute myeloid leukemia
Creators Name:Giacopelli, B. and Wang, M. and Cleary, A. and Wu, Y.Z. and Schultz, A.R. and Schmutz, M. and Blachly, J.S. and Eisfeld, A.K. and Mundy-Bosse, B. and Vosberg, S. and Greif, P.A. and Claus, R. and Bullinger, L. and Garzon, R. and Coombes, K.R. and Bloomfield, C.D. and Druker, B.J. and Tyner, J.W. and Byrd, J.C. and Oakes, C.C.
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.
Keywords:DNA Methylation, Acute Myeloid Leukemia, Mutation, Genetic Promoter Regions
Source:Genome Research
Publisher:Cold Spring Harbor Laboratory Press
Page Range:747-761
Date:May 2021
Official Publication:https://doi.org/10.1101/gr.269233.120
PubMed:View item in PubMed

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