AFF4, a Component of the ELL/P-TEFb Elongation Complex and a Shared Subunit of MLL Chimeras, Can Link Transcription Elongation to Leukemia

被引:453
作者
Lin, Chengqi [1 ]
Smith, Edwin R. [1 ]
Takahashi, Hidehisa [1 ]
Lai, Ka Chun [1 ]
Martin-Brown, Skylar [1 ]
Florens, Laurence [1 ]
Washburn, Michael P. [1 ]
Conaway, Joan W. [1 ,2 ]
Conaway, Ronald C. [1 ,2 ]
Shilatifard, Ali [1 ]
机构
[1] Stowers Inst Med Res, Kansas City, MO 64110 USA
[2] Univ Kansas, Med Ctr, Dept Biochem & Mol Biol, Kansas City, KS 66103 USA
基金
美国国家卫生研究院;
关键词
RNA-POLYMERASE-II; SHOCK GENE-EXPRESSION; HEAT-SHOCK; DROSOPHILA-MELANOGASTER; HISTONE METHYLATION; SIGNALING PATHWAY; CELL-GROWTH; IN-VIVO; P-TEFB; PROTEIN;
D O I
10.1016/j.molcel.2010.01.026
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
Chromosomal translocations; involving the MLL gene are associated with infant acute lymphoblastic and mixed lineage leukemia. There are a large number of translocation partners of MLL that share very little sequence or seemingly functional similarities; however, their translocations into MLL result in the pathogenesis of leukemia. To define the molecular reason why these translocations result in the pathogenesis of leukemia, we purified several of the commonly occurring MILL chimeras. We have identified super elongation complex (SEC) associated with all chimeras purified. SEC includes ELL, P-TEFb, AFF4, and several other factors. AFF4 is required for SEC stability and proper transcription by poised RNA polymerase II in metazoans. Knockdown of AFF4 in leukemic cells shows reduction in MLL chimera target gene expression, suggesting that AFF4/SEC could be a key regulator in the pathogenesis of leukemia through many of the MILL partners.
引用
收藏
页码:429 / 437
页数:9
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