Laboratory for Stem Cell and Regenerative Medicine, The Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, 261053, People's Republic of China.
College of Bioscience and Technology, Weifang Medical University, #21406 Basic Laboratory Building, 7166 Baotongxi Street, Weifang, Shandong Province, 261053, People's Republic of China.
Cell Oncol (Dordr). 2019 Apr;42(2):117-130. doi: 10.1007/s13402-018-0414-4. Epub 2018 Nov 16.
Acute leukemias (AL) with a Mixed Lineage Leukemia (MLL) gene rearrangement (MLLr) represent a group of leukemic entities conferring intermediate to adverse prognoses. Multiple chromatin-associated proteins have been shown to play essential roles during the genesis of MLLr AL. Some chromatin-associated proteins function as negative regulators of MLLr AL whereas others are required for leukemic initiation or maintenance - the latter group constituting potential therapeutic targets. Most of the identified proteins have been functionally analyzed using experimental models with human/murine normal cells transformed by MLL-AF9 or other MLL fusion products, which may recapitulate most but not all aspects of human AML, such as immune system interactions - features of which the importance is rapidly emerging.
Here, we review chromatin-associated proteins fundamental to MLLr AL development, highlighting those with targeting potential by small molecule inhibitors. In particular, we focus on synthetic targeting of multiple chromatin-associated proteins, a strategy that shows superior therapeutic efficacy and offers hope for overcoming drug resistance.
具有混合谱系白血病（MLL）基因重排（MLLr）的急性白血病（AL）是一组具有中等到不良预后的白血病实体。已经表明，多种染色质相关蛋白在 MLLr AL 的发生中发挥着重要作用。一些染色质相关蛋白作为 MLLr AL 的负调节剂发挥作用，而其他蛋白则是白血病起始或维持所必需的 - 后一组构成潜在的治疗靶点。大多数已鉴定的蛋白已使用实验模型进行功能分析，该模型使用人/鼠正常细胞转化为 MLL-AF9 或其他 MLL 融合产物，这可能再现大多数但不是所有人类 AML 的方面，例如免疫系统相互作用 - 其重要性正在迅速显现。
在这里，我们综述了对 MLLr AL 发展至关重要的染色质相关蛋白，强调了那些具有小分子抑制剂靶向潜力的蛋白。特别是，我们专注于多个染色质相关蛋白的合成靶向，这一策略显示出优越的治疗效果，并为克服耐药性提供了希望。
