PXD023139

PXD023139 is an original dataset announced via ProteomeXchange.

Title	Full proteome analysis of WT and Ezh2-KO K562 cells
Description	Chemotherapy resistance is the main impediment in the treatment of acute myeloid leukaemia (AML). Despite rapid advances, the various mechanisms that lead to resistance development remain to be defined in detail. Here we report that loss-of-function mutations (LOF) in the histone methyltransferase EZH2 have the potential to confer resistance against the chemotherapeutic agent cytarabine. We identify seven distinct EZH2 mutations leading to loss of H3K27 trimethylation via multiple mechanisms. Analysis of matched diagnosis and relapse samples reveal a heterogenous regulation of EZH2 and a loss of EZH2 in 50% of patients. We confirm that loss of EZH2 induces resistance against cytarabine in the cell lines HEK293T and K562 as well as in a patient-derived xenograft (PDX) model. Proteomics and transcriptomics analysis reveal that resistance is conferred by upregulation of multiple direct and indirect EZH2 target genes that are involved in apoptosis evasion, augmentation of proliferation and alteration of transmembrane transporter function. Our data indicates, that loss of EZH2 results in upregulation of its target genes, providing the cell with a selective growth advantage, which mediates chemotherapy resistance.
HostingRepository	PRIDE
AnnounceDate	2021-03-15
AnnouncementXML	Submission_2021-03-14_22:42:02.542.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Enes Ugur
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2020-12-15 01:46:50	ID requested
1	2021-03-12 07:42:57	announced
⏵ 2	2021-03-14 22:42:03	announced	2021-03-15: Updated project metadata.

Coorens THH, Oliver TRW, Sanghvi R, Sovio U, Cook E, Vento-Tormo R, Haniffa M, Young MD, Rahbari R, Sebire N, Campbell PJ, Charnock-Jones DS, Smith GCS, Behjati S, Inherent mosaicism and extensive mutation of human placentas. Nature, 592(7852):80-85(2021) [pubmed]

10.1038/S41586-021-03345-1;

submitter keyword: AML, Ezh2, Epigenetics, Human, K562, Cytarabine

Heinrich Leonhardt
contact affiliation	Department of Biology II and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
contact email	h.leonhardt@lmu.de
lab head
Enes Ugur
contact affiliation	Heinrich Leonhardt Lab, Department of Humanbiology & BioImaging, LMU Munich
contact email	ugur@bio.lmu.de
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/2021/03/PXD023139

PRIDE project URI

• PRIDE
  1. PXD023139
     1. Label: PRIDE project
     2. Name: Full proteome analysis of WT and Ezh2-KO K562 cells