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

鉴定 MLL-AF9 融合基因驱动的急性髓系白血病的遗传脆弱性

• 批准号: 241808000
• 负责人: Professor Dr. Stefan Fröhling
• 金额: --
• 依托单位: Nationales Centrum für Tumorerkrankungen (NCT) Heidelberg – DKFZ
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/241808000?language=en
• 关键词: Identification; genetic; vulnerabilities; acute; myeloid

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.

MLL-AF9 融合基因是急性髓系白血病 (AML) 中最常见的遗传改变之一，很难进行靶向治疗。我们发现了 MLL-AF9 与细胞周期调节基因 CDK6 抑制之间的合成致死相互作用，这表明靶向 CDK6 可能为 MLL-AF9 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，我们的目标是深入分析 MLL-AF9 和 CDK6 之间的关系，以致力于将 CDK6 开发为基因型选择性治疗靶点。具体来说，我们将 (1) 使用其他人类和小鼠实验系统研究 MLL-AF9 和 CDK6 之间的相互依赖性，特别关注原代造血细胞的实验； (2) 表征 MLL-AF9 阳性 AML 细胞中 CDK6 耗竭的功能后果，并探索药理 CDK6 抑制的效果； (3) 研究 MLL-AF9 表达与 CDK6 依赖性之间的机制联系。这些研究可能为治疗 MLL 重排白血病提供新方法。