Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.
Master of Science in Biotechnology Graduate Program, Northwestern University, Evanston, Illinois.
Clin Cancer Res. 2019 Jan 1;25(1):222-239. doi: 10.1158/1078-0432.CCR-18-1740. Epub 2018 Sep 17.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Chemotherapy treatments show high response rates but have debilitating effects and carry risk of relapse. Previous work implicated NOTCH1 and other oncogenes. However, direct inhibition of these pathways affects healthy tissues and cancer alike. Our goal in this work has been to identify enzymes active in T-ALL whose activity could be targeted for therapeutic purposes.
To identify and characterize new NOTCH1 druggable partners in T-ALL, we coupled studies of the NOTCH1 interactome to expression analysis and a series of functional analyses in cell lines, patient samples, and xenograft models.
We demonstrate that ubiquitin-specific protease 7 (USP7) interacts with NOTCH1 and controls leukemia growth by stabilizing the levels of NOTCH1 and JMJD3 histone demethylase. is highly expressed in T-ALL and is transcriptionally regulated by NOTCH1. In turn, USP7 controls NOTCH1 levels through deubiquitination. USP7 binds oncogenic targets and controls gene expression through stabilization of NOTCH1 and JMJD3 and ultimately H3K27me3 changes. We also show that USP7 and NOTCH1 bind T-ALL superenhancers, and inhibition of USP7 leads to a decrease of the transcriptional levels of NOTCH1 targets and significantly blocks T-ALL cell growth and .
These results provide a new model for USP7 deubiquitinase activity through recruitment to oncogenic chromatin loci and regulation of both oncogenic transcription factors and chromatin marks to promote leukemia. Our studies also show that targeting USP7 inhibition could be a therapeutic strategy in aggressive leukemia.
T 细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性疾病，影响儿童和成人。化疗治疗显示出高反应率，但具有使人衰弱的作用，并带有复发的风险。先前的工作表明 NOTCH1 和其他癌基因的存在。然而，这些途径的直接抑制会影响健康组织和癌症。我们在这项工作中的目标是确定在 T-ALL 中活跃的酶，这些酶的活性可以作为治疗目的的靶点。
为了鉴定和表征 T-ALL 中 NOTCH1 的新可靶向药物伙伴，我们将 NOTCH1 相互作用组的研究与表达分析以及一系列细胞系、患者样本和异种移植模型中的功能分析相结合。
我们证明了泛素特异性蛋白酶 7（USP7）与 NOTCH1 相互作用，并通过稳定 NOTCH1 和 JMJD3 组蛋白去甲基化酶的水平来控制白血病的生长。在 T-ALL 中高度表达，并受 NOTCH1 转录调控。反过来，USP7 通过去泛素化控制 NOTCH1 水平。USP7 通过稳定 NOTCH1 和 JMJD3 并最终改变 H3K27me3 来结合致癌靶标并控制基因表达。我们还表明，USP7 和 NOTCH1 结合 T-ALL 超级增强子，USP7 的抑制导致 NOTCH1 靶基因的转录水平下降，并显著阻止 T-ALL 细胞生长。
这些结果提供了一个新的模型，用于通过招募到致癌染色质位点以及调节致癌转录因子和染色质标记来促进白血病的 USP7 去泛素酶活性。我们的研究还表明，靶向 USP7 抑制可能是侵袭性白血病的一种治疗策略。
