PXD038908 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Resistance mechanism to Notch inhibition and combination therapy in human T cell acute lymphoblastic leukemia |
Description | Gain-of-function mutations in NOTCH1 are among the most frequent genetic alterations in T cell acute lymphoblastic leukemia (T-ALL), making the Notch signaling pathway a promising therapeutic target for personalized medicine. Yet, a major limitation for long-term success of targeted therapy is relapse due to tumor heterogeneity or acquired resistance. Thus, we performed a genome-wide CRISPR-Cas9 screen to identify prospective resistance mechanisms to pharmacological NOTCH inhibitors and novel targeted combination therapies to efficiently combat T-ALL. Mutational loss of Phosphoinositide-3-Kinase regulatory subunit 1 (PIK3R1) causes resistance to Notch inhibition. PIK3R1 deficiency leads to increased PIK3/Akt signaling which regulates the spliceosome and cell cycle machinery, both at the transcriptional and post-translational level. Moreover, several therapeutic combinations have been identified, where simultaneous targeting of the cyclin-dependent kinases 4 and 6 (CDK4/6) and NOTCH proved to be the most efficacious in T-ALL xenotransplantation models. |
HostingRepository | PRIDE |
AnnounceDate | 2024-01-26 |
AnnouncementXML | Submission_2024-01-26_07:23:00.349.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Romain Hamelin |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | phosphorylated residue |
Instrument | Orbitrap Fusion Lumos |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2022-12-19 03:09:55 | ID requested | |
⏵ 1 | 2024-01-26 07:23:01 | announced | |
Publication List
10.1182/bloodadvances.2023010380; |
Cao L, Ruiz Buend, í, a GA, Fournier N, Liu Y, Armand F, Hamelin R, Pavlou M, Radtke F, Resistance mechanism to Notch inhibition and combination therapy in human T-cell acute lymphoblastic leukemia. Blood Adv, 7(20):6240-6252(2023) [pubmed] |
Keyword List
submitter keyword: combination therapies, PIK3R1,Notch1, resistance mechanisms, T-ALL |
Contact List
Freddy Radtke |
contact affiliation | Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland |
contact email | Freddy.Radtke@epfl.ch |
lab head | |
Romain Hamelin |
contact affiliation | PCF |
contact email | romain.hamelin@epfl.ch |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD038908
- Label: PRIDE project
- Name: Resistance mechanism to Notch inhibition and combination therapy in human T cell acute lymphoblastic leukemia