Oncogenic deubiquitination controls tyrosine kinase signaling and therapy response in acute lymphoblastic leukemia

Jin, Qi; Gutierrez Diaz, Blanca; Pieters, Tim; Zhou, Yalu; Narang, Sonali; Fijalkwoski, Igor; Borin, Cristina; Van Laere, Jolien; Payton, Monique; Cho, Byoung-Kyu; Han, Cuijuan; Sun, Limin; Serafin, Valentina; Yacu, George; Von Loocke, Wouter; Basso, Giuseppe; Veltri, Giulia; Dreveny, Ingrid; Ben-Sahra, Issam; Goo, Young Ah; Safgren, Stephanie L.; Tsai, Yi-Chien; Bornhauser, Beat; Suraneni, Praveen Kumar; Gaspar-Maia, Alexandre; Kandela, Irawati; Van Vlierberghe, Pieter; Crispino, John D.; Tsirigos, Aristotelis; Ntziachristos, Panagiotis

Abstract

Dysregulation of kinase signaling pathways favors tumor cell survival and therapy resistance in cancer. Here, we reveal a posttranslational regulation of kinase signaling and nuclear receptor activity via deubiquitination in T cell acute lymphoblastic leukemia (T-ALL).We observed that the ubiquitin-specific protease 11 (USP11) is highly expressed and associates with poor prognosis in T-ALL. USP11 ablation inhibits leukemia progression in vivo, sparing normal hematopoiesis. USP11 forms a complex with USP7 to deubiquitinate the oncogenic lymphocyte cell-specific protein-tyrosine kinase (LCK) and enhance its activity. Impairment of LCK activity leads to increased glucocorticoid receptor (GR) expression and glucocorticoids sensitivity. Genetic knockout of USP7 improved the antileukemic efficacy of glucocorticoids in vivo. The transcriptional activation of GR target genes is orchestrated by the deubiquitinase activity and mediated via an increase in enhancer-promoter interaction intensity. Our data unveil how dysregulated deubiquitination controls leukemia survival and drug resistance, suggesting previously unidentified therapeutic combinations toward targeting leukemia.

Citation

Jin, Q., Gutierrez Diaz, B., Pieters, T., Zhou, Y., Narang, S., Fijalkwoski, I., …Ntziachristos, P. (2022). Oncogenic deubiquitination controls tyrosine kinase signaling and therapy response in acute lymphoblastic leukemia. Science Advances, 8(49), https://doi.org/10.1126/sciadv.abq8437

• Journal Article Type: Article
• Acceptance Date: Oct 23, 2022
• Online Publication Date: Dec 9, 2022
• Publication Date: Dec 9, 2022
• Deposit Date: Apr 11, 2023
• Publicly Available Date: Apr 18, 2023
• Electronic ISSN: 2375-2548
• Publisher: American Association for the Advancement of Science
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 49
• DOI: https://doi.org/10.1126/sciadv.abq8437
• Keywords: Multidisciplinary
• Public URL: https://nottingham-repository.worktribe.com/output/14602410
• Publisher URL: https://www.science.org/doi/10.1126/sciadv.abq8437