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.激酶信号通路因突变发生失调，可促进肿瘤细胞存活与治疗抗性，且在癌症中十分常见。本研究揭示了急性白血病中通过去泛素化对激酶信号通路及核受体活性进行翻译后调控的全新机制。我们观察到，泛素特异性蛋白酶7（USP7）与泛素特异性蛋白酶11（USP11）形成复合物，对致癌性淋巴细胞特异性蛋白酪氨酸激酶（LCK）进行去泛素化修饰。LCK的去泛素化可调控其活性，进而改变T细胞受体信号通路。LCK活性受损会导致糖皮质激素受体（GR）转录本表达上调，最终引发促凋亡靶基因的转录激活，并在原发性T细胞急性淋巴细胞白血病（T-ALL）患者样本中使细胞对糖皮质激素产生敏感性。促凋亡靶基因（如BCL2L11）的转录激活由去泛素酶活性所调控，并通过增强增强子-启动子相互作用强度介导。本研究阐明了失调的去泛素化如何通过调控信号通路促进癌细胞存活与药物耐药，并提出了靶向白血病的新型治疗联合方案。