TY - JOUR
T1 - USP7 cooperates with NOTch1 to drive the oncogenic transcriptional program in T-cell leukemia
AU - Jin, Qi
AU - Martinez, Carlos A.
AU - Arcipowski, Kelly M.
AU - Zhu, Yixing
AU - Gutierrez-Diaz, Blanca T.
AU - Wang, Kenneth K.
AU - Johnson, Megan R.
AU - Volk, Andrew G.
AU - Wang, Feng
AU - Wu, Jian
AU - Grove, Charles
AU - Wang, Hui
AU - Sokirniy, Ivan
AU - Thomas, Paul M.
AU - Goo, Young Ah
AU - Abshiru, Nebiyu A.
AU - Hijiya, Nobuko
AU - Peirs, Sofie
AU - Vandamme, Niels
AU - Berx, Geert
AU - Goosens, Steven
AU - Marshall, Stacy A.
AU - Rendleman, Emily J.
AU - Takahashi, Yoh hei
AU - Wang, Lu
AU - Rawat, Radhika
AU - Bartom, Elizabeth T.
AU - Collings, Clayton K.
AU - Van Vlierberghe, Pieter
AU - Strikoudis, Alexandros
AU - Kelly, Stephen
AU - Ueberheide, Beatrix
AU - Mantis, Christine
AU - Kandela, Irawati
AU - Bourquin, Jean Pierre
AU - Bornhauser, Beat
AU - Serafin, Valentina
AU - Bresolin, Silvia
AU - Paganin, Maddalena
AU - Accordi, Benedetta
AU - Basso, Giuseppe
AU - Kelleher, Neil L.
AU - Weinstock, Joseph
AU - Kumar, Suresh
AU - Crispino, John D.
AU - Shilatifard, Ali
AU - Ntziachristos, Panagiotis
N1 - Funding Information:
This work was supported by the NIH T32CA080621-11 Oncogenesis and Developmental Biology Training Grant and Cancer Smashers Postdoctoral Fellowship (to K.M. Arcipowski), and by the National Cancer Institute (R00CA188293-02), the American Society of Hematology, the Leukemia Research Foundation, the St. Baldrick's Foundation, the H Foundation, the Gabrielle's Angel Foundation, and the Zell Foundation (to P. Ntziachristos). This work is also supported by AIRC IG 19186 grant to G. Berx. High-throughput sequencing data have been deposited into Gene Expression Omnibus, accession number GSE97435. Proteomics services were performed by the Northwestern proteomics core, generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569. For some of the in vivo studies we collaborated with the Developmental Therapeutics Core (DTC), also supported by Cancer Center Support Grant P30 CA060553 from the National Cancer Institute.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-18-1740
DO - 10.1158/1078-0432.CCR-18-1740
M3 - Article
C2 - 30224337
AN - SCOPUS:85059486336
SN - 1078-0432
VL - 25
SP - 222
EP - 239
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -