USP7 cooperates with NOTch1 to drive the oncogenic transcriptional program in T-cell leukemia

Qi Jin, Carlos A. Martinez, Kelly M. Arcipowski, Yixing Zhu, Blanca T. Gutierrez-Diaz, Kenneth K. Wang, Megan R. Johnson, Andrew G. Volk, Feng Wang, Jian Wu, Charles Grove, Hui Wang, Ivan Sokirniy, Paul M. Thomas, Young Ah Goo, Nebiyu A. Abshiru, Nobuko Hijiya, Sofie Peirs, Niels Vandamme, Geert BerxSteven Goosens, Stacy A. Marshall, Emily J. Rendleman, Yoh hei Takahashi, Lu Wang, Radhika Rawat, Elizabeth T. Bartom, Clayton K. Collings, Pieter Van Vlierberghe, Alexandros Strikoudis, Stephen Kelly, Beatrix Ueberheide, Christine Mantis, Irawati Kandela, Jean Pierre Bourquin, Beat Bornhauser, Valentina Serafin, Silvia Bresolin, Maddalena Paganin, Benedetta Accordi, Giuseppe Basso, Neil L. Kelleher, Joseph Weinstock, Suresh Kumar, John D. Crispino, Ali Shilatifard, Panagiotis Ntziachristos*

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Purpose: 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. Experimental Design: 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. Results: 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. USP7 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 in vitro and in vivo. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)222-239
Number of pages18
JournalClinical Cancer Research
Volume25
Issue number1
DOIs
StatePublished - Jan 1 2019

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Jin, Q., Martinez, C. A., Arcipowski, K. M., Zhu, Y., Gutierrez-Diaz, B. T., Wang, K. K., Johnson, M. R., Volk, A. G., Wang, F., Wu, J., Grove, C., Wang, H., Sokirniy, I., Thomas, P. M., Goo, Y. A., Abshiru, N. A., Hijiya, N., Peirs, S., Vandamme, N., ... Ntziachristos, P. (2019). USP7 cooperates with NOTch1 to drive the oncogenic transcriptional program in T-cell leukemia. Clinical Cancer Research, 25(1), 222-239. https://doi.org/10.1158/1078-0432.CCR-18-1740