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PXD031949

PXD031949 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleOncogenic deubiquitination controls tyrosine kinase signaling and therapy response in acute lymphoblastic leukemia
DescriptionDysregulation 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.
HostingRepositoryMassIVE
AnnounceDate2022-10-31
AnnouncementXMLSubmission_2022-10-31_06:50:54.237.xml
DigitalObjectIdentifier
ReviewLevelNon peer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterCho Byoung-Kyu
SpeciesList scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606;
ModificationListGG
InstrumentLTQ Orbitrap Elite; Q Exactive HF; Orbitrap Fusion
Dataset History
RevisionDatetimeStatusChangeLog Entry
02022-02-28 12:20:38ID requested
12022-10-31 06:50:54announced
Publication List
no publication
Keyword List
submitter keyword: Acute lymphoblastic leukemia, Deubiquitination, Lymphocyte-specific kinase
Contact List
Young Ah Goo
contact affiliationWashington University in St. Louis
contact emailygoo@wustl.edu
lab head
Cho Byoung-Kyu
contact affiliationWashington University in St. Louis
contact emailbyoung-kyu@wustl.edu
dataset submitter
Full Dataset Link List
MassIVE dataset URI
Dataset FTP location
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