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

被引：296

作者：

Li, Sheng ^{[1
,2
,21
]}

Garrett-Bakelman, Francine E. ^{[3
]}

Chung, Stephen S. ^{[4
]}

Sanders, Mathijs A. ^{[5
]}

Hricik, Todd ^{[4
]}

Rapaport, Franck ^{[4
]}

Patel, Jay ^{[4
]}

Dillon, Richard ^{[6
]}

Vijay, Priyanka ^{[7
]}

Brown, Anna L. ^{[8
,9
,10
,11
,12
]}

Perl, Alexander E. ^{[13
]}

Cannon, Joy ^{[13
]}

Bullinger, Lars ^{[14
]}

Luger, Selina ^{[13
]}

Becker, Michael ^{[15
]}

Lewis, Ian D. ^{[8
,9
,11
,12
,16
]}

To, Luen Bik ^{[11
,12
,16
]}

Delwel, Ruud ^{[5
]}

Lowenberg, Bob ^{[5
]}

Doehner, Hartmut ^{[14
]}

Guzman, Monica L. ^{[3
,14
]}

Hassane, Duane C. ^{[3
]}

Roboz, Gail J. ^{[3
]}

Grimwade, David ^{[6
]}

Valk, Peter J. M. ^{[5
]}

D'Andrea, Richard J. ^{[8
,9
,10
,11
,12
]}

Carroll, Martin ^{[13
]}

Park, Christopher Y. ^{[17
,18
]}

Neuberg, Donna ^{[19
]}

Levine, Ross ^{[4
]}

Melnick, Ari M. ^{[3
]}

Mason, Christopher E. ^{[1
,2
,20
]}

机构：

[1] Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA

[2] Weill Cornell Med, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al Sa, New York, NY 10065 USA

[3] Weill Cornell Med, Div Hematol Med Oncol, Dept Med, New York, NY 10065 USA

[4] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA

[5] Erasmus Univ, Med Ctr, Dept Hematol, Rotterdam, Netherlands

[6] Kings Coll London, Dept Med & Mol Genet, Fac Life Sci & Med, London, England

[7] Weill Cornell Med, Triinst Training Program Computat Biol & Med, New York, NY USA

[8] SA Pathol, Ctr Canc Biol, Adelaide, SA, Australia

[9] Univ South Australia, Adelaide, SA, Australia

[10] Univ South Australia, Sch Pharm & Med Sci, Adelaide, SA, Australia

[11] SA Pathol, Dept Hematol, Adelaide, SA, Australia

[12] Royal Adelaide Hosp, Adelaide, SA, Australia

[13] Univ Penn, Div Hematol & Oncol, Philadelphia, PA 19104 USA

[14] Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany

[15] Univ Rochester, Med Ctr, Rochester, NY 14642 USA

[16] Univ Adelaide, Sch Med, Adelaide, SA, Australia

[17] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA

[18] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA

[19] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA

[20] Feil Family Brain & Mind Res Inst, New York, NY USA

[21] Weill Cornell Med, Dept Neurosurg, New York, NY USA

来源：

NATURE MEDICINE | 2016年 / 22卷 / 07期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

CLONAL EVOLUTION; DNA METHYLATION; MUTATIONS RESULT; TET2; FUNCTION; CHEMOTHERAPY; CTCF; AML;

D O I：

10.1038/nm.4125

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Genetic heterogeneity contributes to clinical outcome and progression of most tumors, but little is known about allelic diveisity 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.

引用

页码：792 / 799

页数：8

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