科学家研制出治疗白血病新药

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作者：Mark A. Dawson 来源：《自然》 发布时间：2011-10-9
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英国剑桥大学等机构的研究人员日前报告说，他们研发出一种治疗混合系白血病的新药，动物实验和在试管中对人体细胞进行的实验都显示这种药物有效。
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* ]' J3 C5 a7 G6 a混合系白血病由代号为MLL的基因发生变异引起，变异后的基因会指导生成一种“融合蛋白质”，该蛋白质又会去影响其他基因，最终引发白血病。在这个病变链条中，研究人员发现一个可以干预的环节，即融合蛋白质需要一种代号为BET的蛋白质帮助，才能影响别的基因。
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英国剑桥大学等机构的研究者在英国《自然》杂志网站上报告说，他们找到一种能阻断BET蛋白质功能的化学物质。实验显示，这种名为I－BET151的物质可有效治疗实验鼠所患的混合系白血病，对于在试管中培养的人体病变细胞也有治疗效果。
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研究人员布莱恩·亨特利说，混合系白血病很难治疗，患者常常需要移植骨髓才能活下去，希望本次研究的结果将来能帮助患者摆脱对移植骨髓的依赖。( g* Y% U7 C8 C! j' d1 Q2 r
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据介绍，幼儿所患白血病中大多数都是混合系白血病，成人患者中也有部分是混合系白血病。目前对这种病没有很好的治疗手段，幼儿如果患上混合系白血病，按照目前的常规疗法，两年后患者的存活率只有50%左右。（来源：新华网 黄堃）
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5 W* U1 v% ~$ K* w" |# NInhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia# }( h3 M! Y6 w- E

2 O- u# F- J& ]$ Y8 H0 `0 EMark A. Dawson1, 2, 11 Rab K. Prinjha3, 11 Antje Dittman4, 11 George Giotopoulos1 Marcus Bantscheff4 Wai-In Chan1 Samuel C. Robson2 Chun-wa Chung5 Carsten Hopf4 Mikhail M. Savitski4 Carola Huthmacher4 Emma Gudgin1 Dave Lugo3 Soren Beinke3 Trevor D. Chapman3 Emma J. Roberts3 Peter E. Soden3 Kurt R. Auger6 Olivier Mirguet7 Konstanze Doehner8 Ruud Delwel9 Alan K. Burnett10 Phillip Jeffrey3 Gerard Drewes4 Kevin Lee3, 12 Brian J. P. Huntly1, 11 Tony Kouzarides2, 11
+ W$ ~# H1 g. N* ~1 ]6 @6 G1 \Affiliations Contributions Corresponding authors Journal name: Nature
; l# q# C' [+ \8 ~Year published: (2011) doi:10.1038/nature10509
$ x' P) j# m8 K; X  b0 \Received 29 June 2011 Accepted 30 August 2011 Published online 02 October 2011 . [8 I2 X9 b; e& g4 t  V6 |
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Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies1. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction2, 3. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC2, 3 and the polymerase-associated factor complex (PAFc)4, 5, are associated with the BET family of acetyl-lysine recognizing, chromatin ‘adaptor’ proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL–AF9 and human MLL–AF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.
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* l7 O0 y" `8 }$ Mhttp://www.nature.com/nature/jou ... ll/nature10509.html