PXD013061 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Asparaginase and GSK3A inhibitor treatment of CCRF-CEM cells |
Description | Resistance to asparaginase, an antileukemic enzyme that depletes asparagine, is a common clinical problem. Using a genome-wide CRISPR/Cas9 screen, we found a synthetic lethal interaction between Wnt pathway activation and asparaginase in acute leukemias resistant to this enzyme. Wnt pathway activation induced asparaginase sensitivity in distinct treatment-resistant subtypes of acute leukemia, but not in normal hematopoietic progenitors. Sensitization to asparaginase was mediated by Wnt-dependent stabilization of proteins (Wnt/STOP), which inhibits GSK3-dependent protein ubiquitination and proteasomal degradation, a catabolic source of asparagine. Inhibiting the alpha isoform of GSK3 phenocopied this effect, and pharmacologic GSK3 inhibition profoundly sensitized drug-resistant leukemias to asparaginase. Our findings provide a molecular rationale for activation of Wnt/STOP signaling to improve the therapeutic index of asparaginase. To gain further insights into mechanisms of cytotoxicity of this combination, we applied unbiased mass spectrometry proteomics to CCRF-CEM cells, a human T-cell acute lymphoblastic leukemia cell line, treated with vehicle, asparaginase alone, the GSK3 inhibitor BRD0705 (which phenocopies Wnt/STOP pathway activation), or the combination of asparaginase and BRD0705. |
HostingRepository | PRIDE |
AnnounceDate | 2023-11-14 |
AnnouncementXML | Submission_2023-11-14_08:50:11.319.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Alejandro Gutierrez |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | No PTMs are included in the dataset |
Instrument | LTQ Orbitrap |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2019-03-12 03:47:49 | ID requested | |
1 | 2019-03-29 07:56:49 | announced | |
2 | 2019-04-18 03:48:14 | announced | Updated publication reference for DOI(s): 10.1016/J.CCELL.2019.03.004. |
3 | 2019-05-14 07:18:38 | announced | Updated publication reference for DOI(s): 10.1016/J.CCELL.2019.03.004. |
⏵ 4 | 2023-11-14 08:50:12 | announced | 2023-11-14: Updated project metadata. |
Publication List
Hinze L, Pfirrmann M, Karim S, Degar J, McGuckin C, Vinjamur D, Sacher J, Stevenson KE, Neuberg DS, Orellana E, Stanulla M, Gregory RI, Bauer DE, Wagner FF, Stegmaier K, Gutierrez A, Synthetic Lethality of Wnt Pathway Activation and Asparaginase in Drug-Resistant Acute Leukemias. Cancer Cell, 35(4):664-676.e7(2019) [pubmed] |
Keyword List
submitter keyword: GSK3, leukemia,Asparaginase |
Contact List
Alejandro Gutierrez |
contact affiliation | Division of Hematology/Oncology Boston Children's Hospital Boston, MA, USA |
contact email | alejandro.gutierrez@childrens.harvard.edu |
lab head | |
Alejandro Gutierrez |
contact affiliation | Boston Children's Hospital |
contact email | alejandro.gutierrez@childrens.harvard.edu |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD013061
- Label: PRIDE project
- Name: Asparaginase and GSK3A inhibitor treatment of CCRF-CEM cells