PXD038908

PXD038908 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2022-12-19 03:09:55	ID requested
⏵ 1	2024-01-26 07:23:01	announced

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]

submitter keyword: combination therapies, PIK3R1,Notch1, resistance mechanisms, T-ALL

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

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/2024/01/PXD038908

PRIDE project URI

• PRIDE
  1. PXD038908
     1. Label: PRIDE project
     2. Name: Resistance mechanism to Notch inhibition and combination therapy in human T cell acute lymphoblastic leukemia