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

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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish
Article numberabq8437
JournalScience advances
Volume8
Issue number49
DOIs
StatePublished - 2022
Externally publishedYes

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