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上海士鋒關(guān)于MLL-ENL促進(jìn)造血干細(xì)胞的分化
點(diǎn)擊次數(shù)：901 發(fā)布時(shí)間：2013-5-1
由于ENL和CBX8結(jié)合，造成CBX8無法抑制轉(zhuǎn)錄延長(zhǎng)
轉(zhuǎn)錄延長(zhǎng)的發(fā)生是造成白血病的主要原因，而MLL是造成轉(zhuǎn)錄延長(zhǎng)的關(guān)鍵。此項(xiàng)研究表明，MLL-ENL融合蛋白同樣可以抑制調(diào)?；虮磉_(dá)的PRC1的活性，從而促進(jìn)造血干細(xì)胞的分化。
生化研究表明，融合蛋白MLL-ENL的ENL會(huì)抑制PRC1的CBX8的活性。ENL和CBX8之間的關(guān)系是特異專一的。CBX8會(huì)抑制轉(zhuǎn)錄延長(zhǎng)，但是由于ENL的作用，造成CBX8無法發(fā)揮作用。但是同時(shí)，無法結(jié)合CBX8的MLL-ENL融合蛋白無法有效地激活基因位點(diǎn)，而激活基因位點(diǎn)對(duì)于造血干細(xì)胞的分化是必須的。
此項(xiàng)研究表明，MLL-ENL融合蛋白可能會(huì)加強(qiáng)對(duì)于抑制基因表達(dá)的PRC1的抑制，同時(shí)促進(jìn)造血干細(xì)胞的分化，并導(dǎo)致白血病的發(fā)生。
MLL-ENL Inhibits Polycomb Repressive Complex 1 to Achieve Efficient Transformation of Hematopoietic Cells
Emanuel Maethner,Maria-Paz Garcia-Cuellar,Constanze Breitinger,Sylvia Takacova,Vladimir Divoky,Jay L. Hess,Robert K. Slany
Stimulation of tranｓｃｒｉｐｔional elongation is a key activity of leukemogenic MLL fusion proteins. Here, we provide evidence that MLL-ENL also inhibits Polycomb-mediated silencing as a prerequisite for efficient transformation. Biochemical studies identified ENL as a scaffold that contacted the elongation machinery as well as the Polycomb repressive complex 1 （PRC1） component CBX8. These interactions were mutually exclusive in vitro, corresponding to an antagonistic behavior of MLL-ENL and CBX8 in vivo. CBX8 inhibited elongation in a specific reporter assay