AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia.
AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia.
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DOI：
10.1016/j.molcel.2010.01.026
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发表时间：
2010-02-12
期刊：
影响因子：
16
通讯作者：
Shilatifard, Ali
中科院分区：
文献类型：
--
作者：
Lin, Chengqi;Smith, Edwin R.;Takahashi, Hidehisa;Lai, Ka Chun;Martin-Brown, Skylar;Florens, Laurence;Washburn, Michael P.;Conaway, Joan W.;Conaway, Ronald C.;Shilatifard, Ali
涉及MLL基因的染色体易位与婴儿急性淋巴细胞性白血病和混合性白血病有关。MLL有大量的易位配对，它们的序列或表面上的功能相似性很小，然而，它们易位到MLL导致了白血病的发生。为了确定这些易位导致白血病发病的分子原因，我们纯化了几个常见的MLL嵌合体。我们已经鉴定出一种新的与所有纯化的嵌合体相关的超延长复合体(SEC)。SEC包括ELL、P-TEFb、AFF4等几个因素。在后生动物中，AFF4对于SEC的稳定性和稳定的RNA聚合酶II的正确转录是必需的。在白血病细胞中，AFF4在SEC内的敲除显示MLL嵌合体靶基因表达减少，这表明AFF4/SEC可能通过许多MLL伙伴在白血病的发病机制中发挥关键调节作用。
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 MLL chimeras. We have identified a novel 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 within SEC 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 MLL partners.
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