The heterodimerization domains of MLL-FYRN and FYRC-are potential target structures in t(4;11) leukemia
The heterodimerization domains of MLL-FYRN and FYRC-are potential target structures in t(4;11) leukemia
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DOI：
10.1038/leu.2010.308
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发表时间：
2011-04-01
期刊：
影响因子：
11.4
通讯作者：
Marschalek, R.
中科院分区：
文献类型：
--
作者：
Pless, B.;Oehm, C.;Marschalek, R.
染色体易位t（4;11）（q21;q23）是混合系白血病（MLL）基因的常见遗传畸变，主要与儿科患者的高危急性淋巴细胞白血病（ALL）相关。先前的研究表明，移植了表达AF 4-MLL融合蛋白的造血细胞的小鼠发生proB ALL。AF 4-MLL癌蛋白被Taspase 1介导的水解激活，随后导致切割产物AF 4-MLL的异二聚体。N和MLL。C.这种蛋白质-蛋白质相互作用是由于存在于两种蛋白质片段中的FYRN和FYRC相互作用结构域。异源二聚化随后诱导高分子量蛋白质复合物的形成，该复合物被保护免受SIAH 1/2介导的多泛素化。在这里，我们试图选择性地阻止这一初始异源二聚化步骤，旨在防止AF 4-MLL多蛋白复合物的致癌激活。首先在细菌双杂交系统中，然后在哺乳动物细胞中通过使用生物传感器测定实验确定最小相互作用界面。FYRC结构域或其较小部分的表达导致异二聚体形成的抑制，并阻断AF 4-MLL多蛋白复合物的形成，随后破坏AF 4-MLL癌蛋白。因此，原则上可以特异性靶向AF 4-MLL蛋白。现在可以利用这些知识来设计抑制性诱饵，以破坏AF 4-MLL癌蛋白。Leukemia（2011）25，663-670; doi：10.1038/leu.2010.308; 2011年1月14日在线发表
The chromosomal translocation t(4;11)(q21;q23) is a frequent genetic aberration of the mixed lineage leukemia (MLL) gene, predominantly associated with high-risk acute lymphoblastic leukemia (ALL) in pediatric patients. Previous studies demonstrated that mice transplanted with hematopoietic cells expressing the AF4-MLL fusion protein develop proB ALL. The AF4-MLL oncoprotein becomes activated by Taspase1-mediated hydrolysis, which subsequently leads to a heterodimer of the cleavage products AF4-MLL . N and MLL . C. This protein-protein interaction is due to the FYRN and FYRC interaction domains present in both protein fragments. Heterodimerization subsequently induces high-molecular-weight protein complex formation that is protected against SIAH1/2-mediated polyubiquitinylation. Here, we attempted to selectively block this initial heterodimerization step, aiming to prevent the oncogenic activation of the AF4-MLL multiprotein complex. The minimal interaction interface was experimentally defined first in a bacterial two-hybrid system, and then in mammalian cells by using a biosensor assay. Expression of the FYRC domain, or smaller portions thereof, resulted in the inhibition of heterodimer formation, and blocked AF4-MLL multiprotein complex formation with subsequent destruction of the AF4-MLL oncoprotein. Thus, it is in principle possible to specifically target the AF4-MLL protein. This knowledge can now be exploited to design inhibitory decoys in order to destroy the AF4-MLL oncoprotein. Leukemia (2011) 25, 663-670; doi:10.1038/leu.2010.308; published online 14 January 2011