DOT1L, the H3K79 methyltransferase, is required for MLL-AF9-mediated leukemogenesis

被引:210
作者
Anh Tram Nguyen [1 ,2 ]
Taranova, Olena [1 ,2 ]
He, Jin [1 ,2 ]
Zhang, Yi [1 ,2 ]
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
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)
引用
收藏
页码:6912 / 6922
页数:11
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