PXD026803

PXD026803 is an original dataset announced via ProteomeXchange.

Title	Calreticulin mutated hematopoietic cells are vulnerable to ATR-CHK1 pathway inhibition
Description	Disease frameshift mutations of calreticulin (CALR) are the second most prevalent driver mutations in essential thrombocythemia (ET) and primary myelofibrosis (PMF). To identify potential targeted therapies for CALR mutated myeloproliferative neoplasms, we aimed to search for small molecule drugs that selectively inhibit the growth of CALR mutated cells using high-throughput drug screening. We investigated 89,172 compounds using isogenic cell lines and identified several hits targeting the ATR-CHK1 pathway. The selective inhibitory effect of these candidate compounds was validated in a co-culture assay of CALR mutated and wild type cells. Of the tested hit compounds, CHK1 inhibitors potently depleted CALR mutated cells, allowing CALR wild type cell dominance in the co-culture over time. Neither CALR deficient cells nor JAK2V617F mutated cells showed hypersensitivity to the drug treatment, suggesting that the vulnerability to ATR-CHK1 inhibition is specifically caused by the oncogenic activation by the mutant CALR. CHK1 inhibitors induced replication stress in CALR mutated cells revealed by elevated pan-nuclear staining for γH2AX and hyperphosphorylation of RPA2. They also promoted S-phase cell cycle arrest and blocked the completion of DNA replication in CALR mutated cells. Transcriptomic and phosphoproteomic analyses revealed a replication stress signature caused by the oncogenic CALR mutation, suggesting an intrinsic vulnerability of these cells to CHK1 perturbation. This study indicates that ATR-CHK1 pathway is a potential therapeutic target in CALR mutated hematopoietic cells.
HostingRepository	PRIDE
AnnounceDate	2021-09-07
AnnouncementXML	Submission_2021-09-07_04:14:35.031.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD026803
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Andre Mueller
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue; deamidated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-06-18 06:04:30	ID requested
⏵ 1	2021-09-07 04:14:35	announced

Jia R, Kutzner L, Koren A, Runggatscher K, M, á, jek P, M, ü, ller AC, Schuster M, Bock C, Loizou JI, Kubicek S, Kralovics R, High-throughput drug screening identifies the ATR-CHK1 pathway as a therapeutic vulnerability of CALR mutated hematopoietic cells. Blood Cancer J, 11(7):137(2021) [pubmed]

submitter keyword: Mouse, Calreticulin mutant, ATR-CHK1 pathway, myeloproliferative neoplasms , MPN

Robert Kralovics
contact affiliation	., Department of Laboratory Medicine, Medical University of Vienna, 18-20 Währinger Gürtel, 1090 Vienna, Austria
contact email	robert.kralovics@meduniwien.ac.at
lab head
Andre Mueller
contact affiliation	Research Center for Molecular Medicine of the Austrian Academy of Sciences
contact email	amueller@cemm.oeaw.ac.at
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD026803
     1. Label: PRIDE project
     2. Name: Calreticulin mutated hematopoietic cells are vulnerable to ATR-CHK1 pathway inhibition