PXD046958

PXD046958 is an original dataset announced via ProteomeXchange.

Title	The E3 Ubiquitin Ligase Cul5 Limits HSPC Expansion and Myeloproliferative Disease in Mice
Description	Myeloproliferative Neoplasms (MPNs) are a heterogenous group of hematologic cancers characterized by excessive JAK/STAT signaling. Mutations of JAK2 signaling components are among the most common drivers of MPN, but alterations in Suppressors of Cytokine Signaling (SOCS) proteins have been implicated in MPN pathogenesis and progression. Cullin 5 (Cul5) is an E3 ubiquitin ligase known to work with suppressors of cytokine signaling (SOCS) proteins which regulate the JAK/STAT pathway. Here we report that mice lacking Cul5 in hematopoietic stem and progenitor cells (HSPCs) develop an MPN-like disease with characteristic features including splenomegaly, extramedullary hematopoiesis, thrombocytosis, and anemia. Cul5-deficient HSPCs have higher phospho-STAT5 (pSTAT5) levels following stimulation with IL-3 and outcompete WT HSPCs in bone marrow transplants. Immunoprecipitation of Cul5 in cultured HSPCs showed interactions with STAT5 as well as several well-studied substrate receptors including SOCS2, SOCS6, ASB2, ASB3, ASB6 and CIS, as well as lesser-known WSB1 and LRRC41. Proteome analysis of Lin- Sca-1+ c-kit+ (LSK) cells from Cul5Vav-Cre bone marrow shared many upregulated genes and signatures with MPN patient cells. Finally, treatment with ruxolitinib, a JAK1/2 inhibitor, ameliorated MPN symptoms in Cul5-deficient mice. These studies demonstrate a novel function of Cul5 in hematopoiesis, delineating a contributing role in MPN.
HostingRepository	PRIDE
AnnounceDate	2025-09-08
AnnouncementXML	Submission_2025-09-07_17:29:16.718.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Hossein Fazelinia
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2023-11-14 10:20:27	ID requested
⏵ 1	2025-09-07 17:29:17	announced

10.1172/jci180913;

Tomishima SA, Kim DD, Porter N, Guha I, Dar AA, Ortega-Burgos Y, Roof J, Fazelinia H, Spruce LA, Thom CS, Bowman RL, Oliver PM, The E3 ubiquitin ligase Cul5 regulates hematopoietic stem cell function for steady-state hematopoiesis in mice. J Clin Invest, 135(17):(2025) [pubmed]

submitter keyword: Myeloproliferative Neoplasms, JAK2 signaling, HSPC Expansion, Cul5, E3 Ubiquitin Ligase

Paula M
contact affiliation	Head, Division of Protective Immunity Children’s Hospital of Philadelphia 816F ARC, 3615 Civic Center Blvd Philadelphia, PA 19104
contact email	paulao@pennmedicine.upenn.edu
lab head
Hossein Fazelinia
contact affiliation	Children's Hospital of Philadelphia
contact email	fazeliniah@email.chop.edu
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/2025/09/PXD046958

PRIDE project URI

• PRIDE
  1. PXD046958
     1. Label: PRIDE project
     2. Name: The E3 Ubiquitin Ligase Cul5 Limits HSPC Expansion and Myeloproliferative Disease in Mice