Cell and Molecular Biology Program, University of Michigan, Ann Arbor, Michigan.
Institute for Cancer Genetics, Columbia University, New York, New York.
Blood Cancer Discov. 2020 Sep;1(2):178-197. doi: 10.1158/2643-3230.BCD-20-0026.
Notch activation is highly prevalent among cancers, in particular T-cell acute lymphoblastic leukemia (T-ALL). However, the use of pan-Notch inhibitors to treat cancers has been hampered by adverse effects, particularly intestinal toxicities. To circumvent this barrier in T-ALL, we aimed to inhibit ETS1, a developmentally important T-cell transcription factor previously shown to co-bind Notch response elements. Using complementary genetic approaches in mouse models, we show that ablation of Ets1 leads to strong Notch-mediated suppressive effects on T-cell development and leukemogenesis, but milder intestinal effects than pan-Notch inhibitors. Mechanistically, genome-wide chromatin profiling studies demonstrate that Ets1 inactivation impairs recruitment of multiple Notch-associated factors and Notch-dependent activation of transcriptional elements controlling major Notch-driven oncogenic effector pathways. These results uncover previously unrecognized hierarchical heterogeneity of Notch-controlled genes and points to Ets1-mediated enucleation of Notch-Rbpj transcriptional complexes as a target for developing specific anti-Notch therapies in T-ALL that circumvent the barriers of pan-Notch inhibition.
Notch 激活在癌症中非常普遍，特别是 T 细胞急性淋巴细胞白血病（T-ALL）。然而，使用泛 Notch 抑制剂治疗癌症受到了不良反应的阻碍，特别是肠道毒性。为了克服 T-ALL 中的这一障碍，我们旨在抑制 ETS1，这是一种发育过程中重要的 T 细胞转录因子，先前已被证明与 Notch 反应元件共同结合。通过在小鼠模型中使用互补的遗传方法，我们表明 Ets1 的缺失导致 Notch 对 T 细胞发育和白血病发生的强烈抑制作用，但比泛 Notch 抑制剂的肠道作用更温和。从机制上讲，全基因组染色质谱研究表明，Ets1 的失活会损害多种 Notch 相关因子的募集以及控制主要 Notch 驱动的致癌效应途径的转录元件的 Notch 依赖性激活。这些结果揭示了 Notch 控制的基因以前未被认识的层次异质性，并指出 Ets1 介导的 Notch-Rbpj 转录复合物去核作为开发 T-ALL 中特定抗 Notch 治疗的靶点，该靶点避开了泛 Notch 抑制的障碍。
