Medical Systems Biology, Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, Germany.
Institute for Medical Informatics and Biometry (IMB), Technische Universität Dresden, 01307 Dresden, Germany.
Cells. 2022 Mar 2;11(5):854. doi: 10.3390/cells11050854.
() mutations belong to the most frequent genetic aberrations found in adult acute myeloid leukemia (AML). Recent evidence suggests that these mutations arise early in leukemogenesis, marking leukemic progenitors and stem cells, and persist through consolidation chemotherapy, providing a pool for AML relapse. Currently, there are no therapeutic approaches directed specifically against this cell population. To unravel therapeutically actionable targets in mutant -driven AML cells, we have performed a focused RNAi screen in a panel of 30 primary AML samples, all carrying a R882 mutation. As one of the strongest hits, we identified as a gene essential for proliferation of primary AML cells. We analyzed a publicly available RNA-Seq dataset of primary normal karyotype (NK) AML samples and found a trend towards MDM4 transcript overexpression particularly in -mutant samples. Moreover, we found that the MDM2/4 inhibitor ALRN-6924 impairs growth of primary cells in vitro by inducing cell cycle arrest through upregulation of p53 target genes. Our results suggest that MDM4 inhibition is a potential target in NK-AML patients bearing R882X mutations.
() 突变属于成人急性髓细胞白血病 (AML) 中最常见的遗传异常。最近的证据表明，这些突变在白血病发生早期出现，标记白血病祖细胞和干细胞，并在巩固化疗中持续存在，为 AML 复发提供了一个来源。目前，尚无专门针对该细胞群体的治疗方法。为了在突变驱动的 AML 细胞中揭示可治疗的靶点，我们在 30 个携带 R882 突变的原发性 AML 样本的面板中进行了靶向 RNAi 筛选。作为最强的命中之一，我们发现 是原发性 AML 细胞增殖所必需的基因。我们分析了一个公开的原发性正常核型 (NK) AML 样本的 RNA-Seq 数据集，发现 MDM4 转录本在 突变样本中过度表达的趋势。此外，我们发现 MDM2/4 抑制剂 ALRN-6924 通过上调 p53 靶基因诱导细胞周期停滞，从而在体外抑制 原代细胞的生长。我们的研究结果表明，在携带 R882X 突变的 NK-AML 患者中，抑制 MDM4 可能是一个潜在的治疗靶点。
