PXD036075-3

PXD036075 is an original dataset announced via ProteomeXchange.

Title	Clinical drug response and proteotype profiling elucidates targetable vulnerabilities of myelofibrosis
Description	Myelofibrosis (MF) is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. MF patients frequently carry driver mutations in JAK2 and Calreticulin (CALR) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across MF patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three therapeutic vulnerabilities. First, CALR mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high MAPK-Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous CALR mutations result in high ER stress, responding to ER stressors and UPR inhibition. Overall, our integrated analyses provide a molecularly-motivated roadmap for individualized MF patient treatment.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:05:58.968.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mattheus Wildschut
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos; Q Exactive HF-X; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2022-08-16 05:34:00	ID requested
1	2023-10-14 18:11:16	announced
2	2023-11-14 08:29:55	announced	2023-11-14: Updated project metadata.
⏵ 3	2024-10-22 06:05:59	announced	2024-10-22: Updated project metadata.

10.1038/S41467-023-42101-Z;

submitter keyword: Drug screening,Myelofibrosis, Patient samples, Granulocytes, T-cells, Proteotyping, HSPCs

Berend Snijder
contact affiliation	Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Zurich, Switzerland
contact email	snijder@imsb.biol.ethz.ch
lab head
Mattheus Wildschut
contact affiliation	ETH Zurich / University Hospital Zurich
contact email	wildschut@imsb.biol.ethz.ch
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/2023/10/PXD036075

PRIDE project URI

• PRIDE
  1. PXD036075
     1. Label: PRIDE project
     2. Name: Clinical drug response and proteotype profiling elucidates targetable vulnerabilities of myelofibrosis