PXD013061

PXD013061 is an original dataset announced via ProteomeXchange.

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

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.

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]

submitter keyword: GSK3, leukemia,Asparaginase

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

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://ftp.pride.ebi.ac.uk/pride/data/archive/2019/03/PXD013061

PRIDE project URI

• PRIDE
  1. PXD013061
     1. Label: PRIDE project
     2. Name: Asparaginase and GSK3A inhibitor treatment of CCRF-CEM cells