Identification of genetic vulnerabilities in acute myeloid leukemia driven by the MLL-AF9 fusion gene

MLL-AF 9融合基因是急性髓性白血病（AML）中最常见的遗传改变之一，难以进行治疗靶向。我们已经发现MLL-AF 9和细胞周期调控基因CDK 6的抑制之间的合成致死相互作用，这表明靶向CDK 6可能为MLL-AF 9阳性AML以及可能与其他MLL重排相关的白血病提供实质性治疗窗口。在拟议的项目中，我们的目标是对MLL-AF 9和CDK 6之间的关系进行深入分析，以努力开发CDK 6作为基因型选择性治疗靶点。具体而言，我们将（1）使用额外的人和鼠实验系统研究MLL-AF 9和CDK 6之间的相互依赖性，特别关注原代造血细胞的实验;（2）表征CDK 6耗尽在MLL-AF 9阳性AML细胞中的功能后果并探索药理学CDK 6抑制的作用;以及（3）研究MLL-AF 9表达与CDK 6依赖性之间的机制联系。这些研究可能为MLL重排白血病的治疗提供新的途径。

The MLL-AF9 fusion gene, one of the most common genetic alterations in acute myeloid leukemia (AML), is difficult to target therapeutically. We have discovered a synthetic lethal interaction between MLL-AF9 and suppression of the cell cycle regulatory gene CDK6, suggesting that targeting of CDK6 may provide a substantive therapeutic window in MLL-AF9-positive AML and, possibly, leukemias associated with other MLL rearrangements. In the proposed project, we aim to perform an in-depth analysis of the relationship between MLL-AF9 and CDK6 to work towards the development of CDK6 as a genotype-selective therapeutic target. Specifically, we will (1) investigate the codependence between MLL-AF9 and CDK6 using additional human and murine experimental systems, with particular focus on experiments with primary hematopoietic cells; (2) characterize the functional consequences of CDK6 depletion in MLL-AF9-positive AML cells and explore the effects of pharmacologic CDK6 inhibition; and (3) investigate the mechanistic link between MLL-AF9 expression and CDK6 dependence. These studies may provide a new approach to treating MLL-rearranged leukemia.