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

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.

Emerging Epigenetic and Posttranslational Mechanisms Controlling Resistance to Glucocorticoids in Acute Lymphoblastic Leukemia

“…Mechanistically, USP9X silencing leads to a decrease of MCL1, BCL2 and BCL‐XL levels and an increase in BAX levels 148 . Our teams further demonstrated that the complex of ubiquitin‐specific proteases USP7 and USP11 deubiquitinates LCK and plays a critical role in LCK blocking GR activity 149 . We observed that USP7 and USP11 are highly expressed in T‐ALL and associated with poor disease prognosis.…”

“…In this case, deubiquitination controls the activity and not the levels of LCK, preventing GR activation upon dexamethasone treatment. Indeed, impairment of USP7/11 or LCK activity led to increased NR3C1 expression, chromatin and transcriptional changes in downstream genes, and sensitized cells to treatment with dexamethasone 149 . This study underlined the role of deubiquitination in controlling resistance to therapy.…”

“…148 Our teams further demonstrated that the complex of ubiquitin-specific proteases USP7 and USP11 deubiquitinates LCK and plays a critical role in LCK blocking GR activity. 149 We observed that USP7 and USP11 are highly expressed in T-ALL and associated with poor disease prognosis. Leukemia progression is slowed down by USP11 ablation in vivo, but normal hematopoiesis is preserved.…”

“…Indeed, impairment of USP7/11 or LCK activity led to increased NR3C1 expression, chromatin and transcriptional changes in downstream genes, and sensitized cells to treatment with dexamethasone. 149 This study underlined the role of deubiquitination in controlling resistance to therapy. For instance, it was shown that high expression of USP1 was correlated with poor prognosis in T-ALL patients.…”

“…171 Research conducted by our groups showed that treatment with USP7 inhibitors enhances the binding of GR to BIM IGR and increases chromatin accessibility and enhancer-promoter looping. 149…”