PXD035626

PXD035626 is an original dataset announced via ProteomeXchange.

Title	Using global proteomics to investigate the effect of IQDMA treatment on Leukemic forms of cutaneous T-cell lymphomas (L-CTCL) cells
Description	Leukemic cutaneous T-cell lymphomas (L-CTCL) are lymphoproliferative disorders of skin-homing mature T-cells causing chronic inflammation, tissue destruction, severe infections and sepsis, all linked to poor quality of life and high mortality. Despite numerous sequencing efforts in L-CTCL, recurrent driver mutations have not been identified, but chromosomal losses and gains are frequent and dominant. We integrated genomic landscape analysis with innovative pharmacologic interference studies to identify key vulnerable nodes in L-CTCL. In order to examine IQDMA-specific effects in an unbiased and dose-dependent manner without limiting the analysis to only kinases, we carried out global proteomics profiling in SeAx cells after 24 h treatment with 1, 2.5 and 10 µM IQDMA. The differential proteins affected in response to increasing IQDMA concentrations were found to be related to multiple cellular processes in metabolism, ribosomal RNA processing/modification, protein translation, and surprisingly keratinization.. Dual inhibition of STAT3/5 using small molecule degraders abolished L-CTCL cell growth in vitro. Furthermore, upstream broad range kinase targeting through IQDMA, a newly classified multi-kinase inhibitor, revealed a pharmacologic opportunity to alternatively block the STAT3/5 pathway by inhibiting the PAK2 serine/threonine kinase, which was very effective in patient cells carrying STAT3/5 copy number gains and in vivo in reducing tumor growth and disease dissemination in an intradermal xenograft mouse model. In summary, we conclude that STAT3/5 and PAK2 are new therapy targets to be further explored in L-CTCL.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:40:49.329.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Abootaleb Sedighi
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-07-29 07:17:52	ID requested
1	2023-03-11 02:32:14	announced
⏵ 2	2023-11-14 08:40:54	announced	2023-11-14: Updated project metadata.

Sorger H, Dey S, Vieyra-Garcia PA, P, ö, l, ö, ske D, Teufelberger AR, de Araujo ED, Sedighi A, Graf R, Spiegl B, Lazzeri I, Braun T, Garces de Los Fayos Alonso I, Schlederer M, Timelthaler G, Kodajova P, Pirker C, Surbek M, Machtinger M, Graier T, Perchthaler I, Pan Y, Fink-Puches R, Cerroni L, Ober J, Otte M, Albrecht JD, Tin G, Abdeldayem A, Manaswiyoungkul P, Olaoye OO, Metzelder ML, Orlova A, Berger W, Wobser M, Nicolay JP, Andr, é F, Nguyen VA, Neubauer HA, Fleck R, Merkel O, Herling M, Heitzer E, Gunning PT, Kenner L, Moriggl R, Wolf P, Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T-cell lymphoma. EMBO Mol Med, 14(12):e15200(2022) [pubmed]

submitter keyword: global proteomics, kinase,cutaneous T-cell lymphomas (L-CTCL)

Patrick Gunning
contact affiliation	Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Canada
contact email	patrick.gunning@utoronto.ca
lab head
Abootaleb Sedighi
contact affiliation	Research Associate
contact email	taleb.sedighi@utoronto.ca
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD035626
     1. Label: PRIDE project
     2. Name: Using global proteomics to investigate the effect of IQDMA treatment on Leukemic forms of cutaneous T-cell lymphomas (L-CTCL) cells