DNMT3A mutations mediate the epigenetic reactivation of the leukemogenic factor MEIS1 in acute myeloid leukemia

被引：46

作者：

Ferreira, H. J. ^{[1
]}

Heyn, H. ^{[1
]}

Vizoso, M. ^{[1
]}

Moutinho, C. ^{[1
]}

Vidal, E. ^{[1
]}

Gomez, A. ^{[1
]}

Martinez-Cardus, A. ^{[1
]}

Simo-Riudalbas, L. ^{[1
]}

Moran, S. ^{[1
]}

Jost, E. ^{[2
]}

Esteller, M. ^{[1
,3
,4
]}

机构：

[1] Bellvitge Biomed Res Inst IDIBELL, PEBC, Barcelona, Catalonia, Spain

[2] Rhein Westfal TH Aachen, Fac Med, Dept Hematol Oncol Hemostaseol & Stem Cell Transp, Aachen, Germany

[3] Univ Barcelona, Sch Med, Dept Physiol Sci 2, Barcelona, Catalonia, Spain

[4] ICREA, Barcelona, Catalonia, Spain

来源：

ONCOGENE | 2016年 / 35卷 / 23期

关键词：

AML; GENES; CELL; HOX; METHYLATION; EXPRESSION; TARGETS;

D O I：

10.1038/onc.2015.359

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：

Close to half of de novo acute myeloid leukemia (AML) cases do not exhibit any cytogenetic aberrations. In this regard, distortion of the DNA methylation setting and the presence of mutations in epigenetic modifier genes can also be molecular drivers of the disease. In recent years, somatic missense mutations of the DNA methyltransferase 3A (DNMT3A) have been reported in similar to 20% of AML patients; however, no obvious critical downstream gene has been identified that could explain the role of DNMT3A in the natural history of AML. Herein, using whole-genome bisulfite sequencing and DNA methylation microarrays, we have identified a key gene undergoing promoter hypomethylation-associated transcriptional reactivation in DNMT3 mutant patients, the leukemogenic HOX cofactor MEIS1. Our results indicate that, in the absence of mixed lineage leukemia fusions, an alternative pathway for engaging an oncogenic MEIS1-dependent transcriptional program can be mediated by DNMT3A mutations.

引用

页码：3079 / 3082

页数：4

共 15 条

[1] Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials [J].

Grimwade, David ;

Hills, Robert K. ;

Moorman, Anthony V. ;

Walker, Helen ;

Chatters, Stephen ;

Goldstone, Anthony H. ;

Wheatley, Keith ;

Harrison, Christine J. ;

Burnett, Alan K. .

BLOOD, 2010, 116 (03) :354-365

[2] Decreased DNA methylation in acute myeloid leukemia patients with DNMT3A mutations and prognostic implications of DNA methylation [J].

Hajkova, Hana ;

Markova, Jana ;

Haskovec, Cedrik ;

Sarova, Iveta ;

Fuchs, Ota ;

Kostecka, Arnost ;

Cetkovsky, Petr ;

Michalova, Kyra ;

Schwarz, Jiri .

LEUKEMIA RESEARCH, 2012, 36 (09) :1128-1133

[3] Cell of Origin in AML: Susceptibility to MN1-Induced Transformation Is Regulated by the MEIS1/AbdB-like HOX Protein Complex [J].

Heuser, Michael ;

Yun, Haiyang ;

Berg, Tobias ;

Yung, Eric ;

Argiropoulos, Bob ;

Kuchenbauer, Florian ;

Park, Gyeongsin ;

Hamwi, Iyas ;

Palmqvist, Lars ;

Lai, Courteney K. ;

Leung, Malina ;

Lin, Grace ;

Chaturvedi, Anuhar ;

Thakur, Basant Kumar ;

Iwasaki, Masayuki ;

Bilenky, Mikhail ;

Thiessen, Nina ;

Robertson, Gordon ;

Hirst, Martin ;

Kent, David ;

Wilson, Nicola K. ;

Goettgens, Bertie ;

Eaves, Connie ;

Cleary, Michael L. ;

Marra, Marco ;

Ganser, Arnold ;

Humphries, R. Keith .

CANCER CELL, 2011, 20 (01) :39-52

[4] Low frequency of DNMT3A mutations in pediatric AML, and the identification of the OCI-AML3 cell line as an in vitro model [J].

Hollink, I. H. I. M. ;

Feng, Q. ;

Danen-van Oorschot, A. A. ;

Arentsen-Peters, S. T. C. J. M. ;

Verboon, L. J. ;

Zhang, P. ;

de Haas, V. ;

Reinhardt, D. ;

Creutzig, U. ;

Trka, J. ;

Pieters, R. ;

van den Heuvel-Eibrink, M. M. ;

Wang, J. ;

Zwaan, C. M. .

LEUKEMIA, 2012, 26 (02) :371-373

[5] DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies [J].

Im, A. P. ;

Sehgal, A. R. ;

Carroll, M. P. ;

Smith, B. D. ;

Tefferi, A. ;

Johnson, D. E. ;

Boyiadzis, M. .

LEUKEMIA, 2014, 28 (09) :1774-1783

[6] New insights into MLL gene rearranged acute leukemias using gene expression profiling:: shared pathways, lineage commitment, and partner genes [J].

Kohlmann, A ;

Schoch, C ;

Dugas, M ;

Schnittger, S ;

Hiddemann, W ;

Kern, W ;

Haferlach, T .

LEUKEMIA, 2005, 19 (06) :953-964

[7] Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia [J].

Ley, Timothy J. ;

Miller, Christopher ;

Ding, Li ;

Raphael, Benjamin J. ;

Mungall, Andrew J. ;

Robertson, A. Gordon ;

Hoadley, Katherine ;

Triche, Timothy J., Jr. ;

Laird, Peter W. ;

Baty, Jack D. ;

Fulton, Lucinda L. ;

Fulton, Robert ;

Heath, Sharon E. ;

Kalicki-Veizer, Joelle ;

Kandoth, Cyriac ;

Klco, Jeffery M. ;

Koboldt, Daniel C. ;

Kanchi, Krishna-Latha ;

Kulkarni, Shashikant ;

Lamprecht, Tamara L. ;

Larson, David E. ;

Lin, Ling ;

Lu, Charles ;

McLellan, Michael D. ;

McMichael, Joshua F. ;

Payton, Jacqueline ;

Schmidt, Heather ;

Spencer, David H. ;

Tomasson, Michael H. ;

Wallis, John W. ;

Wartman, Lukas D. ;

Watson, Mark A. ;

Welch, John ;

Wendl, Michael C. ;

Ally, Adrian ;

Balasundaram, Miruna ;

Birol, Inanc ;

Butterfield, Yaron ;

Chiu, Readman ;

Chu, Andy ;

Chuah, Eric ;

Chun, Hye-Jung ;

Corbett, Richard ;

Dhalla, Noreen ;

Guin, Ranabir ;

He, An ;

Hirst, Carrie ;

Hirst, Martin ;

Holt, Robert A. ;

Jones, Steven .

NEW ENGLAND JOURNAL OF MEDICINE, 2013, 368 (22) :2059-2074

[8] DNMT3A Mutations in Acute Myeloid Leukemia. [J].

Ley, Timothy J. ;

Ding, Li ;

Walter, Matthew J. ;

McLellan, Michael D. ;

Lamprecht, Tamara ;

Larson, David E. ;

Kandoth, Cyriac ;

Payton, Jacqueline E. ;

Baty, Jack ;

Welch, John ;

Harris, Christopher C. ;

Lichti, Cheryl F. ;

Townsend, R. Reid ;

Fulton, Robert S. ;

Dooling, David J. ;

Koboldt, Daniel C. ;

Schmidt, Heather ;

Zhang, Qunyuan ;

Osborne, John R. ;

Lin, Ling ;

O'Laughlin, Michelle ;

McMichael, Joshua F. ;

Delehaunty, Kim D. ;

McGrath, Sean D. ;

Fulton, Lucinda A. ;

Magrini, Vincent J. ;

Vickery, Tammi L. ;

Hundal, Jasreet ;

Cook, Lisa L. ;

Conyers, Joshua J. ;

Swift, Gary W. ;

Reed, Jerry P. ;

Alldredge, Patricia A. ;

Wylie, Todd ;

Walker, Jason ;

Kalicki, Joelle ;

Watson, Mark A. ;

Heath, Sharon ;

Shannon, William D. ;

Varghese, Nobish ;

Nagarajan, Rakesh ;

Westervelt, Peter ;

Tomasson, Michael H. ;

Link, Daniel C. ;

Graubert, Timothy A. ;

DiPersio, John F. ;

Mardis, Elaine R. ;

Wilson, Richard K. .

NEW ENGLAND JOURNAL OF MEDICINE, 2010, 363 (25) :2424-2433

[9] Differential expression of Hox, Meis1, and Pbx1 genes in primitive cells throughout murine hematopoietic ontogeny [J].

Pineault, N ;

Helgason, CD ;

Lawrence, HJ ;

Humphries, RK .

EXPERIMENTAL HEMATOLOGY, 2002, 30 (01) :49-57

[10] Differential methylation in CN-AML preferentially targets non-CGI regions and is dictated by DNMT3A mutational status and associated with predominant hypomethylation of HOX genes [J].

Qu, Ying ;

Lennartsson, Andreas ;

Gaidzik, Verena I. ;

Deneberg, Stefan ;

Karimi, Mohsen ;

Bengtzen, Sofia ;

Hoglund, Martin ;

Bullinger, Lars ;

Doehner, Konstanze ;

Lehmann, Soren .

EPIGENETICS, 2014, 9 (08) :1108-1119

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