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

TitleDistinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia.
Publication TypeJournal Article
Year of Publication2016
AuthorsLi S, Garrett-Bakelman FE, Chung SS, Sanders MA, Hricik T, Rapaport F, Patel J, Dillon R, Vijay P, Brown AL, Perl AE, Cannon J, Bullinger L, Luger S, Becker M, Lewis ID, To LBik, Delwel R, Löwenberg B, Döhner H, Döhner K, Guzman ML, Hassane DC, Roboz GJ, Grimwade D, Valk PJM, D'Andrea RJ, Carroll M, Park CY, Neuberg D, Levine R, Melnick AM, Mason CE
JournalNat Med
Volume22
Issue7
Pagination792-9
Date Published2016 07
ISSN1546-170X
KeywordsAdult, Alleles, CpG Islands, Cytosine, Disease Progression, DNA Methylation, Epigenesis, Genetic, Evolution, Molecular, Female, Gene Expression Regulation, Leukemic, Genetic Heterogeneity, High-Throughput Nucleotide Sequencing, Humans, Leukemia, Myeloid, Acute, Male, Middle Aged, Multivariate Analysis, Prognosis, Promoter Regions, Genetic, Proportional Hazards Models, Sequence Analysis, DNA, Sequence Analysis, RNA, Survival Rate
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.

DOI10.1038/nm.4125
Alternate JournalNat. Med.
PubMed ID27322744
PubMed Central IDPMC4938719
Grant ListR01 CA198089 / CA / NCI NIH HHS / United States
K08 CA169055 / CA / NCI NIH HHS / United States
R21 CA176362 / CA / NCI NIH HHS / United States
R01 ES021006 / ES / NIEHS NIH HHS / United States
R01 NS076465 / NS / NINDS NIH HHS / United States
R01 CA172546 / CA / NCI NIH HHS / United States
R01 CA102031 / CA / NCI NIH HHS / United States