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Nat Med. 2016 Jul;22(7):792-9. doi: 10.1038/nm.4125. Epub 2016 Jun 20.

Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia.

Author information

1
Department of Physiology and Biophysics and the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York, USA.
2
Division of Hematology-Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
3
Leukemia Service, Department of Medicine, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
4
Erasmus University Medical Center, Department of Hematology, Rotterdam, the Netherlands.
5
Department of Medical and Molecular Genetics, King's College London, Faculty of Life Sciences and Medicine, London, UK.
6
Tri-Institutional Training Program in Computational Biology and Medicine, Weill Cornell Medicine, New York, New York, USA.
7
Center for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia.
8
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
9
Department of Hematology, SA Pathology and Royal Adelaide Hospital, Adelaide, South Australia, Australia.
10
Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
11
Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
12
University of Rochester Medical Center, Rochester, New York, USA.
13
School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
14
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
15
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
16
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
17
The Feil Family Brain and Mind Research Institute, New York, New York, USA.

Abstract

Genetic heterogeneity contributes to clinical outcome and progression of most tumors, but little is known about allelic diversity for epigenetic compartments, and almost no data exist for acute myeloid leukemia (AML). We examined epigenetic heterogeneity as assessed by cytosine methylation within defined genomic loci with four CpGs (epialleles), somatic mutations, and transcriptomes of AML patient samples at serial time points. We observed that epigenetic allele burden is linked to inferior outcome and varies considerably during disease progression. Epigenetic and genetic allelic burden and patterning followed different patterns and kinetics during disease progression. We observed a subset of AMLs with high epiallele and low somatic mutation burden at diagnosis, a subset with high somatic mutation and lower epiallele burdens at diagnosis, and a subset with a mixed profile, suggesting distinct modes of tumor heterogeneity. Genes linked to promoter-associated epiallele shifts during tumor progression showed increased single-cell transcriptional variance and differential expression, suggesting functional impact on gene regulation. Thus, genetic and epigenetic heterogeneity can occur with distinct kinetics likely to affect the biological and clinical features of tumors.

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