PXD045702-3

PXD045702 is an original dataset announced via ProteomeXchange.

Title	Targetable leukemia dependency on noncanonical PI3Kγ signaling
Description	Phosphoinositide 3-kinase gamma (PI3Kγ) is implicated as a target to repolarize tumor-associated macrophages and promote anti-tumor immune responses in solid cancers. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid, and dendritic lineages. This dependency is characterized by innate inflammatory signaling and elevation of PIK3R5, which encodes a regulatory subunit of PI3Kγ that we find stabilizes the active enzymatic complex when overexpressed. Mechanistically, we identify PAK1 kinase as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency independently of AKT. PI3Kγ inhibition dephosphorylates PAK1, activates a transcriptional network of NFκB-related tumor suppressor genes, and impairs mitochondrial oxidative phosphorylation. We find that treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukemias with activated PIK3R5, either at baseline or by exogenous inflammatory stimulation. Notably, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukemia xenografts with low baseline PIK3R5 expression, as residual leukemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Taken together, our study reveals acute leukemia dependency on a noncanonical PI3Kγ signaling pathway amenable to near-term evaluation in patients using inhibitors already in clinical development.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:34:00.716.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Miguel Prado
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; iodoacetamide derivatized amino-terminal residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-09-26 10:06:40	ID requested
1	2024-03-19 03:50:58	announced
2	2024-06-14 07:07:30	announced	2024-06-14: Updated project metadata.
⏵ 3	2024-10-22 06:34:01	announced	2024-10-22: Updated project metadata.

10.1038/s41586-024-07410-3;

Luo Q, Raulston EG, Prado MA, Wu X, Gritsman K, Whalen KS, Yan K, Booth CAG, Xu R, van Galen P, Doench JG, Shimony S, Long HW, Neuberg DS, Paulo JA, Lane AA, signalling. Nature, 630(8015):198-205(2024) [pubmed]

submitter keyword: leukemia, cancer, TMT, PI3Kγ, PIK3R5, phosphoproteomics

Miguel A. Prado
contact affiliation	Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
contact email	miguel.prado@ispasturias.es
lab head
Miguel Prado
contact affiliation	Harvard Medical School, Boston, USA Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain (lab head)
contact email	miguel.prado@ispasturias.es
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/2024/03/PXD045702

PRIDE project URI

• PRIDE
  1. PXD045702
     1. Label: PRIDE project
     2. Name: Targetable leukemia dependency on noncanonical PI3Kγ signaling