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

t(4;11) 融合蛋白 MLL-AF4 和 AF4-MLL 的分子和药理学抑制

• 批准号: 358233056
• 负责人: Professor Dr. Rolf Marschalek
• 金额: --
• 依托单位: Institut für Pharmazeutische Biologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/358233056?language=en
• 关键词: Molecular; pharmacological; inhibition; 11; fusion

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.

染色体易位t（4;11）与婴儿、儿童和成人的高危急性白血病（proB ALL）相关，然而，预后差（存活率约为40%）。表达的融合蛋白MLL-AF 4和AF 4-MLL已被归类为癌蛋白。我们在过去几年中对这些融合蛋白的病理学的科学研究结果使我们能够预见如何在分子水平或通过使用药理学治疗策略治疗这种类型的白血病。在这里，我们希望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的知识，以选择性地禁用致癌功能衍生自两个融合蛋白（MLL-AF 4和AF 4-MLL）。计划的实验将在适当的细胞培养模型以及患者细胞衍生的PDX小鼠模型中进行，以验证我们的概念。我们的概念明显不同于其他策略，即特异性抑制Menin 1/MLL相互作用，BET蛋白或DOT 1 L，因为这些策略抑制正常细胞中MLL和AF 4的基本功能-这在我们的实验策略中是避免的。