Cancer Science Institute of Singapore, National University of Singapore, 117599.
Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore; VIVA-NUS CenTRAL, Department of Paediatrics, National University of Singapore, 117543.
Haematologica. 2023 Feb 1;108(2):367-381. doi: 10.3324/haematol.2022.280761.
T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy of thymic T-cell precursors. Overexpression of oncogenic transcription factor TAL1 is observed in 40-60% of human T-ALL cases, frequently together with activation of the NOTCH1 and PI3K-AKT pathways. In this study, we performed chemical screening to identify small molecules that can inhibit the enhancer activity driven by TAL1 using the GIMAP enhancer reporter system. Among approximately 3,000 compounds, PIK- 75, a known inhibitor of PI3K and CDK, was found to strongly inhibit the enhancer activity. Mechanistic analysis demonstrated that PIK-75 blocks transcriptional activity, which primarily affects TAL1 target genes as well as AKT activity. TAL1-positive, AKT-activated T-ALL cells were very sensitive to PIK-75, as evidenced by growth inhibition and apoptosis induction, while T-ALL cells that exhibited activation of the JAK-STAT pathway were insensitive to this drug. Together, our study demonstrates a strategy targeting two types of core machineries mediated by oncogenic transcription factors and signaling pathways in T-ALL.
T 细胞急性淋巴细胞白血病（T-ALL）是一种胸腺 T 细胞前体的恶性肿瘤。在 40-60%的人类 T-ALL 病例中观察到致癌转录因子 TAL1 的过表达，通常与 NOTCH1 和 PI3K-AKT 途径的激活有关。在这项研究中，我们使用 GIMAP 增强子报告系统进行了化学筛选，以鉴定能够抑制 TAL1 驱动的增强子活性的小分子。在大约 3000 种化合物中，PIK-75，一种已知的 PI3K 和 CDK 抑制剂，被发现强烈抑制增强子活性。机制分析表明，PIK-75 阻断转录活性，主要影响 TAL1 靶基因以及 AKT 活性。PIK-75 对 TAL1 阳性、AKT 激活的 T-ALL 细胞非常敏感，表现为生长抑制和凋亡诱导，而激活 JAK-STAT 途径的 T-ALL 细胞对该药物不敏感。总之，我们的研究表明了一种针对 T-ALL 中两种类型的核心机制的策略，这些机制由致癌转录因子和信号通路介导。
