Molecular and pharmacological inhibition of the t(4;11) fusion proteins MLL-AF4 and AF4-MLL

染色体易位t（4;11）与婴幼儿、儿童和成人的高危急性白血病（probb ALL）相关，但预后较差（生存率约40%）。表达的融合蛋白MLL-AF4和AF4-MLL已被归类为肿瘤蛋白。在过去的几年里，我们对这些融合蛋白病理的科学研究成果使我们能够预见如何在分子水平上或通过使用药物治疗策略来治疗这种类型的白血病。在这里，我们想在临床前模型中测试我们的知识，然后可以进一步用于临床研究。该项目的先决条件是我们有能力选择性地禁用来自两种融合蛋白（MLL-AF4和AF4-MLL）的致癌功能。计划中的实验将在适当的细胞培养模型中进行，以及在患者细胞衍生的PDX小鼠模型中进行，以验证我们的概念。我们的概念明显区别于其他策略，即特异性抑制Menin1/MLL相互作用，bet -蛋白或DOT1L，因为这些策略抑制了正常细胞中MLL和AF4的基本功能-这在我们的实验策略中是避免的。

The chromosomal translocation t(4;11) is associated with a high-risk acute leukemia (proB ALL) in infants, children and adults, however, with a poor prognosis (survival is ~40%). The expressed fusion proteins MLL-AF4 and AF4-MLL have already been classified as onocproteins. The results of our scientific research during the last years on the pathology of these fusion proteins have brought us to a point where we can foresee how this type of leukemia can be treated at the molecular level or by using pharmacological treatment strategies. Here, we want to test our knowledge in pre¬clinical models, which can then further be used for clinical studies. The prerequisite for this project is our knowledge to selectively disable oncogenic functions deriving from both fusion proteins (MLL-AF4 and AF4-MLL). The planned experiments will be carried out in appropriate cell culture models, as well as in patient-cell derived PDX mouse models for the validation of our concepts. Our concept clearly separates from strategies of others, namely to inhibit specifically the Menin1/MLL interactions, BET-proteins or DOT1L, because those strategies inhibit essential functions of MLL and AF4 in normal cells - which is avoided in our experimental strategy.