Epimutations mimic genomic mutations of DNMT3A in acute myeloid leukemia

被引：46

作者：

Jost, E. ^{[1
]}

Lin, Q. ^{[2
]}

Weidner, C. I. ^{[3
]}

Wilop, S. ^{[1
]}

Hoffmann, M. ^{[1
]}

Walenda, T. ^{[3
]}

Schemionek, M. ^{[1
]}

Herrmann, O. ^{[1
]}

Zenke, M. ^{[2
]}

Bruemmendorf, T. H. ^{[1
]}

Koschmieder, S. ^{[1
]}

Wagner, W. ^{[3
]}

机构：

[1] Rhein Westfal TH Aachen, Sch Med, Dept Oncol Hematol & Stem Cell Transplantat, D-52074 Aachen, Germany

[2] Rhein Westfal TH Aachen, Sch Med, Inst Biomed Engn Cell Biol, D-52074 Aachen, Germany

[3] Rhein Westfal TH Aachen, Sch Med, Helmholtz Inst Biomed Engn Stem Cell Biol & Cellu, D-52074 Aachen, Germany

来源：

LEUKEMIA | 2014年 / 28卷 / 06期

关键词：

acute myeloid leukemia; de novo methyltransferase DNMT3A; mutation; epimutation; DNA methylation; epigenomics; DNA METHYLTRANSFERASE 3A; GENE-EXPRESSION PROFILE; SOMATIC MUTATIONS; HOX GENES; IN-VITRO; METHYLATION; DISTINCT; CANCER; STEM; BRCA1;

D O I：

10.1038/leu.2013.362

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Mutations in the genetic sequence of the DNA de novo methyltransferase DNMT3A (DNA methyltransferase 3A) are found in many patients with acute myeloid leukemia (AML). They lead to dysfunction of DNMT3A protein and represent a marker for poor prognosis. Effects of genetic mutations can be mimicked by epigenetic modifications in the DNA methylation (DNAm) pattern. Using DNAm profiles of the Cancer Genome Atlas Research Network (TCGA), we identified aberrant hypermethylation at an internal promoter region of DNMT3A, which occurred in about 40% of AML patients. Bisulfite pyrosequencing assays designed for this genomic region validated hypermethylation specifically in a subset of our AML samples. High DNAm levels at this site are particularly observed in samples without genetic mutations in DNMT3A. Epimutations and mutations of DNMT3A were associated with related gene expression changes such as upregulation of the homeobox genes in HOXA and HOXB clusters. Furthermore, epimutations in DNMT3A were enriched in patients with poor or intermediate cytogenetic risk, and in patients with shorter event-free survival and overall survival (OS). Taken together, aberrant DNA hypermethylation within the DNMT3A gene, in analogy to DNMT3A mutations, is frequently observed in AML and both modifications seem to be useful for risk stratification or choice of therapeutic regimen.

引用

页码：1227 / 1234

页数：8

共 47 条

[1] Acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc+ AML) shows a distinct gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance [J].

Alcalay, M ;

Tiacci, E ;

Bergomas, R ;

Bigerna, B ;

Venturini, E ;

Minardi, SP ;

Meani, N ;

Diverio, D ;

Bernard, L ;

Tizzoni, L ;

Volorio, S ;

Luzi, L ;

Colombo, E ;

Lo Coco, F ;

Mecucci, C ;

Falini, B ;

Pelicci, PG .

BLOOD, 2005, 106 (03) :899-902

[2] Epimutation and cancer: A new carcinogenic mechanism of Lynch syndrome (Review) [J].

Banno, Kouji ;

Kisu, Iori ;

Yanokura, Megumi ;

Tsuji, Kosuke ;

Masuda, Kenta ;

Ueki, Arisa ;

Kobayashi, Yusuke ;

Yamagami, Wataru ;

Nomura, Hiroyuki ;

Tominaga, Eiichiro ;

Susumu, Nobuyuki ;

Aoki, Daisuke .

INTERNATIONAL JOURNAL OF ONCOLOGY, 2012, 41 (03) :793-797

[3] Integrated genomic analyses of ovarian carcinoma [J].

Bell, D. ;

Berchuck, A. ;

Birrer, M. ;

Chien, J. ;

Cramer, D. W. ;

Dao, F. ;

Dhir, R. ;

DiSaia, P. ;

Gabra, H. ;

Glenn, P. ;

Godwin, A. K. ;

Gross, J. ;

Hartmann, L. ;

Huang, M. ;

Huntsman, D. G. ;

Iacocca, M. ;

Imielinski, M. ;

Kalloger, S. ;

Karlan, B. Y. ;

Levine, D. A. ;

Mills, G. B. ;

Morrison, C. ;

Mutch, D. ;

Olvera, N. ;

Orsulic, S. ;

Park, K. ;

Petrelli, N. ;

Rabeno, B. ;

Rader, J. S. ;

Sikic, B. I. ;

Smith-McCune, K. ;

Sood, A. K. ;

Bowtell, D. ;

Penny, R. ;

Testa, J. R. ;

Chang, K. ;

Dinh, H. H. ;

Drummond, J. A. ;

Fowler, G. ;

Gunaratne, P. ;

Hawes, A. C. ;

Kovar, C. L. ;

Lewis, L. R. ;

Morgan, M. B. ;

Newsham, I. F. ;

Santibanez, J. ;

Reid, J. G. ;

Trevino, L. R. ;

Wu, Y. -Q. ;

Wang, M. .

NATURE, 2011, 474 (7353) :609-615

[4] High density DNA methylation array with single CpG site resolution [J].

Bibikova, Marina ;

Barnes, Bret ;

Tsan, Chan ;

Ho, Vincent ;

Klotzle, Brandy ;

Le, Jennie M. ;

Delano, David ;

Zhang, Lu ;

Schroth, Gary P. ;

Gunderson, Kevin L. ;

Fan, Jian-Bing ;

Shen, Richard .

GENOMICS, 2011, 98 (04) :288-295

[5] Dnmt3a is essential for hematopoietic stem cell differentiation [J].

Challen, Grant A. ;

Sun, Deqiang ;

Jeong, Mira ;

Luo, Min ;

Jelinek, Jaroslav ;

Berg, Jonathan S. ;

Bock, Christoph ;

Vasanthakumar, Aparna ;

Gu, Hongcang ;

Xi, Yuanxin ;

Liang, Shoudan ;

Lu, Yue ;

Darlington, Gretchen J. ;

Meissner, Alexander ;

Issa, Jean-Pierre J. ;

Godley, Lucy A. ;

Li, Wei ;

Goodell, Margaret A. .

NATURE GENETICS, 2012, 44 (01) :23-U43

[6] Mechanistic Insights on the Inhibition of C5 DNA Methyltransferases by Zebularine [J].

Champion, Christine ;

Guianvarc'h, Dominique ;

Senamaud-Beaufort, Catherine ;

Jurkowska, Renata Z. ;

Jeltsch, Albert ;

Ponger, Loic ;

Arimondo, Paola B. ;

Guieysse-Peugeot, Anne-Laure .

PLOS ONE, 2010, 5 (08)

[7]

Dobrovic A, 1997, CANCER RES, V57, P3347

[8] Commonly altered genomic regions in acute myeloid leukemia are enriched for somatic mutations involved in chromatin remodeling and splicing [J].

Dolnik, Anna ;

Engelmann, Julia C. ;

Scharfenberger-Schmeer, Maren ;

Mauch, Julian ;

Kelkenberg-Schade, Sabine ;

Haldemann, Berit ;

Fries, Tamara ;

Kroenke, Jan ;

Kuehn, Michael W. M. ;

Paschka, Peter ;

Kayser, Sabine ;

Wolf, Stephan ;

Gaidzik, Verena I. ;

Schlenk, Richard F. ;

Ruecker, Frank G. ;

Doehner, Hartmut ;

Lottaz, Claudio ;

Doehner, Konstanze ;

Bullinger, Lars .

BLOOD, 2012, 120 (18) :E83-E92

[9] The role of HOX genes in malignant myeloid disease [J].

Eklund, Elizabeth A. .

CURRENT OPINION IN HEMATOLOGY, 2007, 14 (02) :85-89

[10] Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study [J].

Fenaux, Pierre ;

Mufti, Ghulam J. ;

Hellstrom-Lindberg, Eva ;

Santini, Valeria ;

Finelli, Carlo ;

Giagounidis, Aristoteles ;

Schoch, Robert ;

Gattermann, Norbert ;

Sanz, Guillermo ;

List, Alan ;

Gore, Steven D. ;

Seymour, John F. ;

Bennett, John M. ;

Byrd, John ;

Backstrom, Jay ;

Zimmerman, Linda ;

McKenzie, David ;

Beach, C. L. ;

Silverman, Lewis R. .

LANCET ONCOLOGY, 2009, 10 (03) :223-232

← 1 2 3 4 5 →