Deubiquitinases: Pro-oncogenic Activity and Therapeutic Targeting in Acute Leukemia

Dysregulation of kinase signaling pathways via mutations favors tumor cell survival and resistance to therapy and it is common in cancer. In our work we reveal a novel mechanism of posttranslational regulation of kinase signaling and nuclear receptor activity via deubiquitination in acute leukemia. We observed that the ubiquitin specific protease 7 (USP7) forms a complex with USP11 to deubiquitinate oncogenic lymphocyte cell-specific protein tyrosine kinase (LCK). Deubiquitination of LCK controls its activity, thereby altering T cell receptor signaling. Impairment of LCK activity leads to increased expression of the glucocorticoid receptor (GR) transcript, culminating into transcriptional activation of pro-apoptotic target genes and sensitizes cells to glucocorticoids in primary T cell acute lymphoblastic leukemia (T-ALL) patient samples. The transcriptional activation of pro-apoptotic target genes, such as BCL2L11, is orchestrated by the deubiquitinase activity and mediated via an increase in enhancer-promoter interaction intensity. Our data unveil how dysregulated deubiquitination controls signaling pathways, leading to cancer cell survival and drug non-response, and suggest novel therapeutic combinations towards targeting leukemia.