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首页> 外文期刊>Molecular and Cellular Biology >MLL-AFX Requires the Transcriptional Effector Domains of AFX To Transform Myeloid Progenitors and Transdominantly Interfere with Forkhead Protein Function
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MLL-AFX Requires the Transcriptional Effector Domains of AFX To Transform Myeloid Progenitors and Transdominantly Interfere with Forkhead Protein Function

机译：MLL-AFX需要AFX的转录效应子域来转化髓样祖细胞并主要干扰前叉蛋白功能。

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MLL-AFX is a fusion gene created by t(X;11) chromosomal translocations in a subset of acute leukemias of either myeloid or lymphoid derivation. It codes for a chimeric protein consisting of MLL fused to AFX, a forkhead transcription factor that normally regulates genes involved in apoptosis and cell cycle progression. We demonstrate here that forced expression of MLL-AFX enhances the self-renewal of hematopoietic progenitors in vitro and induces acute myeloid leukemias after long latencies in syngeneic recipient mice. MLL-AFX interacts with the transcriptional coactivator CBP, which is also a fusion partner for MLL in human leukemias. A potent minimal transactivation domain (CR3) at the C terminus of AFX mediates interactions with the KIX domain of CBP and is necessary for transformation of myeloid progenitors by MLL-AFX. However, CR3 alone is not sufficient, suggesting that simple acquisition of a transactivation domain per se does not activate the oncogenic potential of MLL. Rather, two conserved transcriptional effector domains (CR2 and CR3) of AFX are required for full oncogenicity of MLL-AFX and also endow it with the potential to competitively interfere with transcription and apoptosis mediated by wild-type forkhead proteins. Furthermore, a dominant-negative mutant of AFX containing CR2 and CR3 enhances the growth of myeloid progenitors in vitro, although considerably less effectively than does MLL-AFX. Taken together, these data suggest that recruitment of transcriptional cofactors utilized by forkhead proteins is a critical requirement for oncogenic action of MLL-AFX, which may impact both MLL- and forkhead-dependent transcriptional pathways.
机译： MLL-AFX 是由t（X; 11）染色体易位在髓样或淋巴样衍生的急性白血病子集中产生的融合基因。它编码一种由MLL融合到AFX的嵌合蛋白，AFX是一种叉头转录因子，通常调节涉及凋亡和细胞周期进程的基因。我们在这里证明，MLL-AFX的强制表达增强了体外造血祖细胞的自我更新，并在同系受体小鼠中长期潜伏后诱导了急性髓细胞性白血病。 MLL-AFX与转录共激活因子CBP相互作用，CBP也是人类白血病中MLL的融合伴侣。 AFX C末端的有效最小反式激活结构域（CR3）介导与CBP KIX结构域的相互作用，这对于通过MLL-AFX转化骨髓祖细胞是必需的。然而，仅CR3是不够的，这表明简单地获得反式激活结构域本身并不能激活MLL的致癌潜力。而是，AFX的两个保守转录效应域（CR2和CR3）是MLL-AFX的完全致癌性所必需的，并且还具有潜在竞争性干扰野生型叉头蛋白介导的转录和凋亡的潜力。此外，含有CR2和CR3的AFX的显性负突变体在体外增强了髓系祖细胞的生长，尽管其效率远低于MLL-AFX。综上所述，这些数据表明叉头蛋白利用的转录辅因子的募集是MLL-AFX致癌作用的关键要求，这可能会影响MLL依赖和叉头依赖的转录途径。

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