TY - JOUR
T1 - Oncogenic deubiquitination controls tyrosine kinase signaling and therapy response in acute lymphoblastic leukemia
AU - Jin, Qi
AU - Diaz, Blanca Gutierrez
AU - Pieters, Tim
AU - Zhou, Yalu
AU - Narang, Sonali
AU - Fijalkwoski, Igor
AU - Borin, Cristina
AU - Van Laere, Jolien
AU - Payton, Monique
AU - Cho, Byoung Kyu
AU - Han, Cuijuan
AU - Sun, Limin
AU - Serafin, Valentina
AU - Yacu, George
AU - Von Loocke, Wouter
AU - Basso, Giuseppe
AU - Veltri, Giulia
AU - Dreveny, Ingrid
AU - Ben-Sahra, Issam
AU - Goo, Young Ah
AU - Safgren, Stephanie L.
AU - Tsai, Yi Chien
AU - Bornhauser, Beat
AU - Suraneni, Praveen Kumar
AU - Gaspar-Maia, Alexandre
AU - Kandela, Irawati
AU - Van Vlierberghe, Pieter
AU - Crispino, John D.
AU - Tsirigos, Aristotelis
AU - Ntziachristos, Panagiotis
N1 - Publisher Copyright:
© 2022 The Authors.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
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U2 - 10.1126/sciadv.abq8437
DO - 10.1126/sciadv.abq8437
M3 - Article
C2 - 36490346
AN - SCOPUS:85143917448
SN - 2375-2548
VL - 8
JO - Science Advances
JF - Science Advances
IS - 49
M1 - abq8437
ER -