MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L

被引：717

作者：

Bernt, Kathrin M. ^{[1
,2
]}

Zhu, Nan ^{[1
,2
]}

Sinha, Amit U. ^{[1
,2
]}

Vempati, Sridhar ^{[1
,2
]}

Faber, Joerg ^{[3
]}

Krivtsov, Andrei V. ^{[1
,2
]}

Feng, Zhaohui ^{[1
,2
]}

Punt, Natalie ^{[1
,2
]}

Daigle, Amanda ^{[1
,2
]}

Bullinger, Lars ^{[4
]}

Pollock, Roy M. ^{[5
]}

Richon, Victoria M. ^{[5
]}

Kung, Andrew L. ^{[1
,2
,6
]}

Armstrong, Scott A. ^{[1
,2
,6
]}

机构：

[1] Harvard Univ, Childrens Hosp, Sch Med, Div Hematol Oncol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA

[3] Johannes Gutenberg Univ Mainz, D-05131 Mainz, Germany

[4] Univ Ulm, D-98091 Ulm, Germany

[5] Epizyme Inc, Cambridge, MA 02139 USA

[6] Harvard Stem Cell Inst, Boston, MA 02138 USA

来源：

CANCER CELL | 2011年 / 20卷 / 01期

关键词：

METHYLTRANSFERASE GENE EZH2; MIXED-LINEAGE LEUKEMIA; ACUTE MYELOID-LEUKEMIA; HISTONE METHYLTRANSFERASE; MYELODYSPLASTIC SYNDROMES; SOMATIC MUTATIONS; TRANSCRIPTION; LEUKEMOGENESIS; EXPRESSION; CHROMATIN;

D O I：

10.1016/j.ccr.2011.06.010

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the Mixed Lineage Leukemia (MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSCs. Inactivation of Dot1l led to downregulation of direct MLL-AF9 targets and an MLL translocation-associated gene expression signature, whereas global gene expression remained largely unaffected. Suppression of MLL translocation-associated gene expression corresponded with dependence of MLL-AF9 leukemia on Dot1l in vivo. These data point to DOT1L as a potential therapeutic target in MLL-rearranged leukemia.

引用

页码：66 / 78

页数：13

共 47 条

[41] Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia [J].

Schlenk, Richard F. ;

Doehner, Konstanze ;

Krauter, Juergen ;

Froehling, Stefan ;

Corbacioglu, Andrea ;

Bullinger, Lars ;

Habdank, Marianne ;

Spaeth, Daniela ;

Morgan, Michael ;

Benner, Axel ;

Schlegelberger, Brigitte ;

Heil, Gerhard ;

Ganser, Arnold ;

Doehner, Hartmut .

NEW ENGLAND JOURNAL OF MEDICINE, 2008, 358 (18) :1909-1918

[42] Linking Cell Cycle to Histone Modifications: SBF and H2B Monoubiquitination Machinery and Cell-Cycle Regulation of H3K79 Dimethylation [J].

Schulze, Julia M. ;

Jackson, Jessica ;

Nakanishi, Shima ;

Gardner, Jennifer M. ;

Hentrich, Thomas ;

Haug, Jeff ;

Johnston, Mark ;

Jaspersen, Sue L. ;

Kobor, Michael S. ;

Shilatifard, Ali .

MOLECULAR CELL, 2009, 35 (05) :626-641

[43] DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells [J].

Steger, David J. ;

Lefterova, Martina I. ;

Ying, Lei ;

Stonestrom, Aaron J. ;

Schupp, Michael ;

Zhuo, David ;

Vakoc, Adam L. ;

Kim, Ja-Eun ;

Chen, Junjie ;

Lazar, Mitchell A. ;

Blobel, Gerd A. ;

Vakoc, Christopher R. .

MOLECULAR AND CELLULAR BIOLOGY, 2008, 28 (08) :2825-2839

[44] The Wnt/β-Catenin Pathway Is Required for the Development of Leukemia Stem Cells in AML [J].

Wang, Yingzi ;

Krivtsov, Andrei V. ;

Sinha, Amit U. ;

North, Trista E. ;

Goessling, Wolfram ;

Feng, Zhaohui ;

Zon, Leonard I. ;

Armstrong, Scott A. .

SCIENCE, 2010, 327 (5973) :1650-1653

[45] A Higher-Order Complex Containing AF4 and ENL Family Proteins with P-TEFb Facilitates Oncogenic and Physiologic MLL-Dependent Transcription [J].

Yokoyama, Akihiko ;

Lin, Min ;

Naresh, Alpana ;

Kitabayashi, Issay ;

Cleary, Michael L. .

CANCER CELL, 2010, 17 (02) :198-212

[46] Hoxa9 and Meis1 are key targets for MLL-ENL-mediated cellular immortalization [J].

Zeisig, BB ;

Milne, T ;

García-Cuéllar, MP ;

Schreiner, S ;

Martin, ME ;

Fuchs, U ;

Borkhardt, A ;

Chanda, SK ;

Walker, J ;

Soden, R ;

Hess, JL ;

Slany, RK .

MOLECULAR AND CELLULAR BIOLOGY, 2004, 24 (02) :617-628

[47] Dot1a-AF9 complex mediates histone H3 Lys-79 hypermethylation and repression of ENaCα in an aldosterone-sensitive manner [J].

Zhang, Wenzheng ;

Xia, Xuefeng ;

Reisenauer, Mary Rose ;

Hemenway, Charles S. ;

Kone, Bruce C. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (26) :18059-18068

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