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

Published: 16 November 2021| Version 1 | DOI: 10.17632/55v76yw529.1
Blanca Gutierrez


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.



Northwestern University - Chicago


Biochemistry, Protein-Tyrosine Kinase, Ubiquitylation, Acute Leukemia