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

Item Type:	Article
Title:	Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia
Creators Name:	Li, S. and Garrett-Bakelman, F.E. and Chung, S.S. and Sanders, M.A. and Hricik, T. and Rapaport, F. and Patel, J. and Dillon, R. and Vijay, P. and Brown, A.L. and Perl, A.E. and Cannon, J. and Bullinger, L. and Luger, S. and Becker, M. and Lewis, I.D. and To, L.B. and Delwel, R. and Löwenberg, B. and Döhner, H. and Döhner, K. and Guzman, M.L. and Hassane, D.C. and Roboz, G.J. and Grimwade, D. and Valk, P.J.M. and D'Andrea, R.J. and Carroll, M. and Park, C.Y. and Neuberg, D. and Levine, R. and Melnick, A.M. and Mason, C.E.
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.
Keywords:	Acute Myeloid Leukemia, Alleles, CpG Islands, Cytosine, DNA Methylation, DNA Sequence Analysis, Disease Progression, Genetic Epigenesis, Genetic Heterogeneity, Genetic Promoter Regions, High-Throughput Nucleotide Sequencing, Leukemic Gene Expression Regulation, Molecular Evolution, Multivariate Analysis, Prognosis, Proportional Hazards Models, Survival Rate
Source:	Nature Medicine
ISSN:	1078-8956
Publisher:	Nature Publishing Group
Volume:	22
Number:	7
Page Range:	792-9
Date:	July 2016
Additional Information:	Copyright © 2016 Nature America, Inc. All rights reserved.
Official Publication:	https://doi.org/10.1038/nm.4125
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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