PXD033953

PXD033953 is an original dataset announced via ProteomeXchange.

Title	A network-based approach reveals a novel mechanism of resistance to TKI-therapy in AML
Description	Internal tandem duplications (ITDs) in the FLT3 gene are frequently identified and confer a poor prognosis in patient affected by acute myeloid leukemia (AML). The insertion site of the ITDs in FLT3 significantly impacts the sensitivity to tyrosine kinase inhibitors (TKIs) therapy, affecting patient’s clinical outcome. To decipher the molecular mechanisms driving the different sensitivity to TKIs therapy of FLT3-ITD cells, we used high-sensitive mass spectrometry-based (phospho)proteomics and deep sequencing. Here, we developed a novel generally-applicable data analysis strategy, dubbed “Signaling Profiler”, that supports the integration of unbiased large-scale datasets with literature-derived signaling networks. The approach resulted in the generation of FLT3-ITDs specific predictive models and reveales a crucial and conserved role of the WEE1-CDK1 axis in TKIs resistance. Remarkably, pharmacological inhibition of the WEE1 kinase significantly synergizes and strengths the pro-apoptotic effect of TKIs therapy in cell lines and patient-derived primary blasts. In conclusion, this work proposes a new molecular mechanism of TKIs resistance in AML and suggests a combination therapy as option to improve therapeutic efficacy.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:25:59.926.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Natalie Krahmer
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2022-05-18 04:01:33	ID requested
1	2023-03-10 18:23:36	announced
⏵ 2	2023-11-14 08:26:00	announced	2023-11-14: Updated project metadata.

Massacci G, Venafra V, Latini S, Bica V, Pugliese GM, Graziosi S, Klingelhuber F, Krahmer N, Fischer T, Mougiakakos D, Boettcher M, Perfetto L, Sacco F, A key role of the WEE1-CDK1 axis in mediating TKI-therapy resistance in FLT3-ITD positive acute myeloid leukemia patients. Leukemia, 37(2):288-297(2023) [pubmed]

submitter keyword: tyrosine kinase inhibitors, Ba/F3 cells,acute myeloid leukemia, midostaurin, FLT3, mouse, phosphoproteomics, TKI, quizartinib, AML

Natalie Krahmer
contact affiliation	Institute for Diabetes and Obesity, Helmholtz Zentrum München, 85764 Neuherberg, Germany German Center for Diabetes Research, Neuherberg, Germany
contact email	natalie.krahmer@helmholtz-muenchen.de
lab head
Natalie Krahmer
contact affiliation	Helmholtz Center Munich
contact email	natalie.krahmer@helmholtz-muenchen.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/2023/03/PXD033953

PRIDE project URI

• PRIDE
  1. PXD033953
     1. Label: PRIDE project
     2. Name: A network-based approach reveals a novel mechanism of resistance to TKI-therapy in AML