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PXD045702 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleTargetable leukemia dependency on noncanonical PI3Kγ signaling
DescriptionPhosphoinositide 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.
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterMiguel Prado
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListphosphorylated residue; iodoacetamide derivatized amino-terminal residue
InstrumentOrbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-09-26 10:06:40ID requested
12024-03-19 03:50:58announced
22024-06-14 07:07:30announced2024-06-14: Updated project metadata.
Publication List
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]
Keyword List
submitter keyword: leukemia, cancer, TMT, PI3Kγ, PIK3R5, phosphoproteomics
Contact List
Miguel A. Prado
contact affiliationInstituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
contact emailmiguel.prado@ispasturias.es
lab head
Miguel Prado
contact affiliationHarvard Medical School, Boston, USA Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain (lab head)
contact emailmiguel.prado@ispasturias.es
dataset submitter
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Dataset FTP location
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