PXD031949-1
PXD031949 is an original dataset announced via ProteomeXchange.
Dataset Summary
| Title | Oncogenic deubiquitination controls tyrosine kinase signaling and therapy response in acute lymphoblastic leukemia |
| Description | Dysregulation of kinase signaling pathways via mutations favors tumor cell survival and resistance to therapy and it is common in cancer. Here, we reveal a novel mechanism of post-translational regulation of kinase signaling and nuclear receptor activity via deubiquitination in acute leukemia. We observed that the ubiquitin specific protease 11 (USP11) is highly expressed in lymphoblastic leukemia and associates with poor prognosis in this disease. USP11 ablation inhibits leukemia growth in vitro and in vivo, sparing normal hematopoiesis and thymus development, suggesting that USP11 could be a therapeutic target in leukemia. USP11 forms a complex with USP7 to deubiquitinate the 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 transcript, culminating into transcriptional activation of pro-apoptotic target genes, and sensitizes cells to glucocorticoids in primary T cell leukemia 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. Pharmacological inhibition of USP7 or genetic knockout of USP7 in combination treatment of glucocorticoid displayed improved anti-T-ALL efficacy in vivo. 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. |
| HostingRepository | MassIVE |
| AnnounceDate | 2022-10-31 |
| AnnouncementXML | Submission_2022-10-31_06:50:54.237.xml |
| DigitalObjectIdentifier | |
| ReviewLevel | Non peer-reviewed dataset |
| DatasetOrigin | Original dataset |
| RepositorySupport | Supported dataset by repository |
| PrimarySubmitter | Cho Byoung-Kyu |
| SpeciesList | scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606; |
| ModificationList | GG |
| Instrument | LTQ Orbitrap Elite; Q Exactive HF; Orbitrap Fusion |
Dataset History
| Revision | Datetime | Status | ChangeLog Entry |
|---|---|---|---|
| 0 | 2022-02-28 12:20:38 | ID requested | |
| ⏵ 1 | 2022-10-31 06:50:54 | announced |
Publication List
| no publication |
Keyword List
| submitter keyword: Acute lymphoblastic leukemia, Deubiquitination, Lymphocyte-specific kinase |
Contact List
| Young Ah Goo | |
|---|---|
| contact affiliation | Washington University in St. Louis |
| contact email | ygoo@wustl.edu |
| lab head | |
| Cho Byoung-Kyu | |
| contact affiliation | Washington University in St. Louis |
| contact email | byoung-kyu@wustl.edu |
| dataset submitter | |
Full Dataset Link List
| MassIVE dataset URI |
| Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://massive.ucsd.edu/MSV000088930/ |
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