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DOT1L, the H3K79 methyltransferase, is required for MLL-AF9-mediated leukemogenesis
被引:210
作者:

Anh Tram Nguyen
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Univ N Carolina, Howard Hughes Med Inst, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
Univ N Carolina, Dept Biochem & Biophys, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA Univ N Carolina, Howard Hughes Med Inst, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

Taranova, Olena
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机构:
Univ N Carolina, Howard Hughes Med Inst, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
Univ N Carolina, Dept Biochem & Biophys, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA Univ N Carolina, Howard Hughes Med Inst, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

He, Jin
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Univ N Carolina, Howard Hughes Med Inst, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
Univ N Carolina, Dept Biochem & Biophys, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA Univ N Carolina, Howard Hughes Med Inst, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

Zhang, Yi
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Univ N Carolina, Howard Hughes Med Inst, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
Univ N Carolina, Dept Biochem & Biophys, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA Univ N Carolina, Howard Hughes Med Inst, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
机构:
[1] Univ N Carolina, Howard Hughes Med Inst, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
[2] Univ N Carolina, Dept Biochem & Biophys, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
来源:
关键词:
MIXED-LINEAGE LEUKEMIA;
ACUTE MYELOID-LEUKEMIA;
HOX GENE-EXPRESSION;
MLL FUSION PARTNERS;
TRANSCRIPTIONAL ELONGATION;
HISTONE METHYLATION;
RETINOBLASTOMA-PROTEIN;
PAF1;
COMPLEX;
CHROMATIN;
TRANSFORMATION;
D O I:
10.1182/blood-2011-02-334359
中图分类号:
R5 [内科学];
学科分类号:
1002 ;
100201 ;
摘要:
Chromosomal translocations of the mixed lineage leukemia (MLL) gene are a common cause of acute leukemias. The oncogenic function of MLL fusion proteins is, in part, mediated through aberrant activation of Hoxa genes and Meis1, among others. Here we demonstrate using a tamoxifen-inducible Cre-mediated loss of function mouse model that DOT1L, an H3K79 methyltransferase, is required for both initiation and maintenance of MLL-AF9-induced leukemogenesis in vitro and in vivo. Through gene expression and chromatin immunoprecipitation analysis we demonstrate that mistargeting of DOT1L, subsequent H3K79 methylation, and up-regulation of Hoxa and Meis1 genes underlie the molecular mechanism of how DOT1L contributes to MLL-AF9-mediated leukemogenesis. Our study not only provides the first in vivo evidence for the function of DOT1L in leukemia, but also reveals the molecular mechanism for DOT1L in MLL-AF9 mediated leukemia. Thus, DOT1L may serve as a potential therapeutic target for the treatment of leukemia caused by MLL translocations. (Blood. 2011;117(25):6912-6922)
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页码:6912 / 6922
页数:11
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