PXD019619

PXD019619 is an original dataset announced via ProteomeXchange.

Title	Development of novel combination treatments in AML guided by proteomics profiling
Description	Acute promyelocytic leukaemia (APL) can be cured by the co-administration of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA). These small molecules relieve the differentiation blockade of the cancerous promyelocytes and trigger their maturation into functional neutrophils, which are physiologically primed for apoptosis. This normalization therapy uses low dose treatments and represents a compelling alternative to cytotoxic anticancer chemotherapy. However, the serendipitous discovery of this combination treatment prevented the establishment of methodologies to screen for novel combination treatments consisting of inducers of differentiation and other metallopharmaceuticals. Here, we present an experimental framework that enables interrogating the suitability, directionality and extent of normalization of novel combination treatments. Since the endpoint of this anticancer treatment is remodelling of cancer phenotypes, this approach requires a mechanism-driven understanding of the drug-induced cellular adaptions along the path to mature neutrophils. For this purpose, label-free quantification proteomics is used to probe the proteome changes upon differentiation and metal(-loid) treatment on the molecular level in a panel of ATRA-responsive and ATRA-non-responsive acute myeloid leukaemia (AML) cell lines, including APL. The induction of differentiation was confirmed by the up-regulation of canonical surface markers (e.g. CD11β) and validated by flow cytometry. The regulation of key transcription factors in this panel of AML cell lines reflects their position in the myeloid differentiation cascade (e.g. SPI1, GFI-1 and CEBPE). The additive/synergistic contributions of ATO to the combination treatment were thoroughly characterized and include changes in metabolic activities, as well as protein signatures related to management of reactive oxygen species and an integrated stress response. The latter two are also characteristic for the organoruthenium-based drug candidate plecstatin-1, which was recently shown to modulate the scaffold protein plectin. The combination of differentiation-induction and plecstatin-1 treatment featured a striking similarity in the responsiveness of the AML cancer cells compared to ATO+ATRA. It turned out to be at least equivalent in the regulation of key processes underlying normalization therapy in AML with granulocytic maturation. By exploiting response patterns of AML cancer cells induced by the ATO+ATRA combination treatment, this approach may allow identifying novel small molecule combinations, which may have the potential to achieve normalization and thus therapeutic benefit beyond APL.
HostingRepository	PRIDE
AnnounceDate	2024-10-08
AnnouncementXML	Submission_2024-10-08_11:40:06.814.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD019619
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Christopher Gerner
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	Oxidation; Acetyl; Carbamidomethyl; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2020-06-06 15:01:44	ID requested
⏵ 1	2024-10-08 11:40:07	announced

Meier-Menches SM, Neuditschko B, Janker L, Gerner MC, Schmetterer KG, Reichle A, Gerner C, . Front Chem, 10():826346(2022) [pubmed]

10.6019/PXD019619;

10.3389/fchem.2022.826346;

submitter keyword: AML, arsenic trioxide, cancer, APL, proteomics, differentiation, normalization, metal, plecstatin-1, ruthenium

Christopher Gerner
contact affiliation	Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria. Joint Metabolome Facility, University of Vienna and Medical University of Vienna, Vienna, Austria.
contact email	christopher.gerner@univie.ac.at
lab head
Christopher Gerner
contact affiliation	University of Vienna
contact email	christopher.gerner@univie.ac.at
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/2022/02/PXD019619

PRIDE project URI

• PRIDE
  1. PXD019619
     1. Label: PRIDE project
     2. Name: Development of novel combination treatments in AML guided by proteomics profiling