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USP7 cooperates with NOTCH1 to drive the oncogenic transcriptional program in T-cell leukemia

(2019) CLINICAL CANCER RESEARCH. 25(1). p.222-239
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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.
Keywords
ACUTE LYMPHOBLASTIC-LEUKEMIA, SMALL-MOLECULE INHIBITOR, GENE-EXPRESSION, SELECTIVE-INHIBITION, JMJD3 CONTRIBUTES, TUMOR-SUPPRESSOR, ANALYSIS REVEALS, SUPER-ENHANCERS, UBIQUITIN, HAUSP

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Citation

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MLA
Jin, Qi et al. “USP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-cell Leukemia.” CLINICAL CANCER RESEARCH 25.1 (2019): 222–239. Print.
APA
Jin, Q., Martinez, C. A., Arcipowski, K. M., Zhu, Y., Gutierrez-Diaz, B. T., Wang, K. K., Johnson, M. R., et al. (2019). USP7 cooperates with NOTCH1 to drive the oncogenic transcriptional program in T-cell leukemia. CLINICAL CANCER RESEARCH, 25(1), 222–239.
Chicago author-date
Jin, Qi, Carlos A Martinez, Kelly M Arcipowski, Yixing Zhu, Blanca T Gutierrez-Diaz, Kenneth K Wang, Megan R Johnson, et al. 2019. “USP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-cell Leukemia.” Clinical Cancer Research 25 (1): 222–239.
Chicago author-date (all authors)
Jin, Qi, 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 Berx, Steven Goossens, 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, and Panagiotis Ntziachristos. 2019. “USP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-cell Leukemia.” Clinical Cancer Research 25 (1): 222–239.
Vancouver
1.
Jin Q, Martinez CA, Arcipowski KM, Zhu Y, Gutierrez-Diaz BT, Wang KK, et al. USP7 cooperates with NOTCH1 to drive the oncogenic transcriptional program in T-cell leukemia. CLINICAL CANCER RESEARCH. 2019;25(1):222–39.
IEEE
[1]
Q. Jin et al., “USP7 cooperates with NOTCH1 to drive the oncogenic transcriptional program in T-cell leukemia,” CLINICAL CANCER RESEARCH, vol. 25, no. 1, pp. 222–239, 2019.
@article{8581162,
  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.},
  author       = {Jin, Qi and Martinez, Carlos A and Arcipowski, Kelly M and Zhu, Yixing and Gutierrez-Diaz, Blanca T and Wang, Kenneth K and Johnson, Megan R and Volk, Andrew G and Wang, Feng and Wu, Jian and Grove, Charles and Wang, Hui and Sokirniy, Ivan and Thomas, Paul M and Goo, Young Ah and Abshiru, Nebiyu A and Hijiya, Nobuko and Peirs, Sofie and Vandamme, Niels and Berx, Geert and Goossens, Steven and Marshall, Stacy A and Rendleman, Emily J and Takahashi, Yoh-hei and Wang, Lu and Rawat, Radhika and Bartom, Elizabeth T and Collings, Clayton K and Van Vlierberghe, Pieter and Strikoudis, Alexandros and Kelly, Stephen and Ueberheide, Beatrix and Mantis, Christine and Kandela, Irawati and Bourquin, Jean-Pierre and Bornhauser, Beat and Serafin, Valentina and Bresolin, Silvia and Paganin, Maddalena and Accordi, Benedetta and Basso, Giuseppe and Kelleher, Neil L and Weinstock, Joseph and Kumar, Suresh and Crispino, John D and Shilatifard, Ali and Ntziachristos, Panagiotis},
  issn         = {1078-0432},
  journal      = {CLINICAL CANCER RESEARCH},
  keywords     = {ACUTE LYMPHOBLASTIC-LEUKEMIA,SMALL-MOLECULE INHIBITOR,GENE-EXPRESSION,SELECTIVE-INHIBITION,JMJD3 CONTRIBUTES,TUMOR-SUPPRESSOR,ANALYSIS REVEALS,SUPER-ENHANCERS,UBIQUITIN,HAUSP},
  language     = {eng},
  number       = {1},
  pages        = {222--239},
  title        = {USP7 cooperates with NOTCH1 to drive the oncogenic transcriptional program in T-cell leukemia},
  url          = {http://dx.doi.org/10.1158/1078-0432.ccr-18-1740},
  volume       = {25},
  year         = {2019},
}

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