Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia

被引：217

作者：

Guenther, Matthew G. ^{[1
]}

Lawton, Lee N. ^{[1
]}

Rozovskaia, Tatiana ^{[2
]}

Frampton, Garrett M. ^{[1
,3
]}

Levine, Stuart S. ^{[1
]}

Volkert, Thomas L. ^{[1
]}

Croce, Carlo M. ^{[4
,5
]}

Nakamura, Tatsuya ^{[4
,5
]}

Canaani, Eli ^{[2
]}

Young, Richard A. ^{[1
,3
]}

机构：

[1] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[2] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel

[3] MIT, Dept Biol, Cambridge, MA 02139 USA

[4] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA

[5] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA

来源：

GENES & DEVELOPMENT | 2008年 / 22卷 / 24期

关键词：

Chromatin; epigenetic; genome-wide; leukemia; stem cell; transcription;

D O I：

10.1101/gad.1741408

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Mixed-lineage leukemia (MLL) fusion proteins are potent inducers of leukemia, but how these proteins generate aberrant gene expression programs is poorly understood. Here we show that the MLL-AF4 fusion protein occupies developmental regulatory genes important for hematopoietic stem cell identity and self-renewal in human leukemia cells. These MLL-AF4-bound regions have grossly altered chromatin structure, with histone modifications catalyzed by trithorax group proteins and DOT1 extending across large domains. Our results define direct targets of the MLL fusion protein, reveal the global role of epigenetic misregulation in leukemia, and identify new targets for therapeutic intervention in cancer.

引用

页码：3403 / 3408

页数：6

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